Compositions and methods for treating hyperkalemia

ABSTRACT

The present invention is directed to compositions and methods of removing potassium or treating hyperkalemia by administering pharmaceutical compositions of cation exchange polymers with low crosslinking for improved potassium excretion and for beneficial physical properties to increase patient compliance.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. provisionalapplication No. 62/096,447, filed Dec. 23, 2014, the entire contents ofwhich are incorporated herein by reference in its entirety

FIELD OF INVENTION

The present invention relates to compositions and methods of removingpotassium from the gastrointestinal track, including methods of treatinghyperkalemia, by administration of crosslinked cation exchange polymerswith a low level of crosslinking for improved potassium excretion andfor improved patient tolerance and compliance.

BACKGROUND OF THE INVENTION

Potassium is the most abundant cation in the intracellular fluid andplays an important role in normal human physiology, especially withregard to the firing of action potential in nerve and muscle cells(Giebisch G. Am J Physiol. 1998, 274(5), F817-33). Total body potassiumcontent is about 50 mmol/kg of body weight, which translates toapproximately 3500 mmols of potassium in a 70 kg adult (Ahmed, J. andWeisberg, L. S. Seminars in Dialysis 2001, 14(5), 348-356). The bulk oftotal body potassium is intracellular (˜98%), with only approximately 70mmol (˜2%) in the extracellular space (Giebisch, G. H., Kidney Int. 200262(5), 1498-512). This large differential between intracellularpotassium (˜120-140 mmol/L) and extracellular potassium (˜4 mmol/L)largely determines the resting membrane potential of cells. As aconsequence, very small absolute changes in the extracellular potassiumconcentration will have a major effect on this ratio and consequently onthe function of excitable tissues (muscle and nerve) (Weiner, I. D. andWingo, C. S., J. Am. Soc. Nephrol. 1998, 9, 1535-1543). Extracellularpotassium levels are therefore tightly regulated.

Two separate and cooperative systems participate in potassiumhomeostasis, one regulating external potassium balance (the body parityof potassium intake vs. potassium elimination) while the other regulatesinternal potassium balance (distribution between intracellular andextracellular fluid compartments) (Giebisch, Kidney Int. 2002).Intracellular extracellular balance provides short-term management ofchanges in serum potassium, and is primarily driven physiologically bythe action of Na⁺, K⁺-ATPase “pumps,” which use the energy of ATPhydrolysis to pump Na and K against their concentration gradients(Giebisch, Kidney Int. 2002). Almost all cells possess an Na⁺, K⁺-ATPase(Palmer, B. F., Clin. J. Am. Soc. Nephrol. 2015, 10(6), 1050-60). Bodyparity is managed by elimination mechanisms via the kidney andgastrointestinal tract: in healthy kidneys, 90-95% of the dailypotassium load is excreted through the kidneys with the balanceeliminated in the feces (Ahmed, Seminars in Dialysis 2001).

Due to the fact that intracellular/extracellular potassium ratio(K_(i):K_(e) ratio) is the major determinant of the resting membranepotential of cells, small changes in K_(e) (i.e., serum [K]) haveprofound effects on the function of electrically active tissues, such asmuscle and nerve. Potassium and sodium ions drive action potentials innerve and muscle cells by actively crossing the cell membrane andshifting the membrane potential, which is the difference in electricalpotential between the exterior and interior of the cell. In addition toactive transport, K⁺ can also move passively between the extracellularand intracellular compartments. An overload of passive K⁺ transport,caused by higher levels of blood potassium, depolarizes the membrane inthe absence of a stimulus. Excess serum potassium, known ashyperkalemia, can disrupt the membrane potential in cardiac cells thatregulate ventricular conduction and contraction. Clinically, the effectsof hyperkalemia on cardiac electrophysiology are of greatest concernbecause they can cause arrhythmias and death (Kovesdy, C. P., Nat. Rev.Nephrol. 2014, 10(11), 653-62). Since the bulk of body parity ismaintained by renal excretion, it is therefore to be expected that askidney function declines, the ability to manage total body potassiumbecomes impaired.

The balance and regulation of potassium in the blood requires anappropriate level of intake through food and the effective eliminationvia the kidneys and digestive tract. Under non-disease conditions, theamount of potassium intake equals the amount of elimination, andhormones such as aldosterone act in the kidneys to stimulate the removalof excess potassium (Palmer, B. F. Clin. J. Am. Soc. Nephrol. 2015,10(6), 1050-60). The principal mechanism through which the kidneysmaintain potassium homeostasis is the secretion of potassium into thedistal convoluted tubule and the proximal collecting duct. In healthyhumans, serum potassium levels are tightly controlled within the narrowrange of 3.5 to 5.0 mEq/L (Macdonald, J. E. and Struthers. A. D. J. Am.Coll. of Cardiol. 2004, 43(2), 155-61). As glomerular filtration rate(GFR) decreases, the ability of the kidneys to maintain serum potassiumlevels in a physiologically normal range is increasingly jeopardized.Studies suggest that the kidneys can adjust to a decrease in the numberof nephrons by increasing potassium secretion by the surviving nephrons,and remain able to maintain normokalemia. However, as kidney functioncontinues to decline these compensatory mechanisms cannot respond topotassium load and serum K increases (Kovesdy, Nat. Rev. Nephrol. 2014).Potassium homeostasis is generally maintained in patients with advancedCKD until the glomerular filtration rate (GFR; a measure of kidneyfunction) falls below 10-15 mL/min. At this point, compensatoryincreases in the secretory rate of K+ in remaining nephrons cannot keepup with potassium load (Palmer, J. Am. Soc. Nephrol. 2015). Excessivelevels of potassium build up in the extracellular fluid, hence leadingto hyperkalemia.

Hyperkalemia is a clinically significant electrolyte abnormality thatcan cause severe electrophysiological disturbances, including cardiacarrhythmias and death. Hyperkalemia is defined as a serum potassiumlevel above the normal range, typically >5.0 mmol/L (Kovesdy, Nat. Rev.Nephrol. 2014). Moderate hyperkalemia (serum potassium above 6.0 mEq/L)has been reported to have a 1-day mortality rate up to 30 times higherthan that of patients with serum potassium less than 5.5 mEq/L (Einhorn,L. M., et als. Arch Intern Med. 2009, 169(12), 1156-1162). Severehyperkalemia (serum K+ of at least 6.5 mmol/L) is a potentiallylife-threatening electrolyte disorder that has been reported to occur in1% to 10% of all hospitalized patients and constitutes a medicalemergency requiring immediate treatment (An, J. N. et al., Critical Care2012, 16, R225). Hyperkalemia is caused by deficiencies in potassiumexcretion, and since the kidney is the primary mechanism of potassiumremoval, hyperkalemia commonly affects patients with kidney diseasessuch as chronic kidney disease (CKD; Einhorn, Arch Intern Med. 2009) orend-stage renal disease (ESRD; Ahmed, Seminars in Dialysis 2001).However, episodes of hyperkalemia can occur in patients with normalkidney function, where it is still a life-threatening condition. Forexample, in hospitalized patients, hyperkalemia has been associated withincreased mortality in patients both with and without CKD (Fordjour, K.N., et al Am. J. Med. Sci. 2014, 347(2), 93-100).

While CKD is the most common predisposing condition for hyperkalemia,the mechanisms driving hyperkalemia typically involve a combination offactors, such as increased dietary potassium intake, disordereddistribution of potassium between intracellular and extracellularcompartments and abnormalities in potassium excretion. These mechanismscan be modulated by a variety of factors with causality outside of CKD.These include the presence of other comorbidities, such as type 2diabetes mellitus (T2DM), cardiovascular disease (CVD) of the use ofco-medications that can disrupt potassium homeostasis as side effects,such as blockade of the renin-angiotensin-aldosterone system (RAAS).These contributing factors to hyperkalemia are described below.

In clinical practice, CKD is the most common predisposing condition forhyperkalemia (Kovesdy, Nat. Rev. Nephrol. 2014). Other commonpredisposing conditions, often comorbidities with CKD, include both type2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), both ofwhich are linked to the development of hyperkalemia through differentmechanisms. Insulin deficiency and hypertonicity caused by hyperglycemiain patients with diabetes contributes to an inability to disperse highacute potassium loads into the intracellular space. Furthermore,diabetes mellitus is associated with hyporeninemic hypoaldosteronism andthe resultant inability to upregulate tubular potassium secretion(Kovesdy, Nat. Rev. Nephrol. 2014). Cardiovascular disease (CVD) andother associated conditions, such as acute myocardial ischaemia, leftventricular hypertrophy and congestive heart failure (CHF), requirevarious medical treatments that have been linked to hyperkalaemia. Forexample, β-adrenergic-receptor blockers, which have beneficialantihypertensive effects via modulation of heart rate and cardiaccontractility, contribute to hyperkalemia through inhibition of cellularadrenergic receptor-dependent potassium translocation, causing adecreased ability to redistribute potassium to the intracellular space(Weir, M. A., et al., Clin. J. Am. Soc. Nephrol. 2010, 5, 1544-15515).Heparin treatment, used to manage or prevent blood clots in CVD, hasalso been linked to hyperkalemia through decreased production ofaldosterone (Edes, T. E., et al., Arch. Intern. Med. 1985, 145,1070-72)). Cardiac glycosides such as digoxin—used to help controlatrial fibrillation and atrial flutter—inhibit cardiac Na⁺/K⁺-ATPase,but also modulate the related Na⁺/K⁺-APTases in the nephrons. This caninhibit the ability of the kidney to secrete potassium into thecollecting duct and can also cause hyperkalemia.

Hyperkalemia occurs especially frequently in patients with CKD who aretreated with certain classes of medications, such asangiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptorblockers (ARBs) or other inhibitors of the renin-angiotensin-aldosteronesystem (RAAS) (Kovesdy, Nat. Rev. Nephrol. 2014). The RAAS is importantfor the regulation of blood pressure, and the maximum doses of RAASinhibitors are widely recommended for patients with hypertension, heartfailure (HF), chronic kidney disease (CKD), and diabetes. Large outcomestudies have shown that RAAS inhibitors can significantly decreasehospitalization, morbidity, and mortality in these patients. In patientswith CKD, RAAS inhibition is beneficial for some of the commoncomorbidities, such as congestive heart failure (CHF). However,inhibition of the RAAS pathway also promotes potassium retention and isa major cause of hyperkalemia. Even in populations without CKD, RAASinhibitor monotherapy (treatment with a single agent) has an incidenceof hyperkalemia of <2%, but this increased to ˜5% in patients receivingdual-agent RAAS inhibitor therapy. This is further exacerbated in CKDpatients, where the incidence of hyperkalemia rises to 5-10% when dualtherapy is administered (Bakris, G. L., et al., Kid. Int. 2000, 58,2084-92, Weir, Clin. J. Am. Soc. Nephrol. 2010). It is therefore oftendifficult or impossible to continue RAAS inhibitor therapy over extendedperiods of time. Hyperkalemia is perhaps the most important cause of theintolerance to RAAS inhibitors observed in patients with CKD. As aconsequence, hyperkalemia has led to the suboptimal use of RAASinhibitors in the treatment of serious diseases such as CKD and heartfailure (Kovesdy, Nat. Rev. Nephrol. 2014).

Congestive heart failure patients, especially those taking RAASinhibitors, are another large group that is at risk of developinglife-threatening levels of serum potassium. The decreased heart outputand corresponding low blood flow through the kidneys, coupled withinhibition of aldosterone, can lead to chronic hyperkalemia.Approximately 5.7 million individuals in the US have congestive heartfailure (Roger, V. L., et al., Circulation. 2012, 125, 188-197). Most ofthese are taking at least one RAAS inhibitor, and studies show that manyare taking a suboptimal dose, often due to hyperkalemia (Choudhry, N. K.et al, Pharmacoepidem. Dr. S. 2008, 17, 1189-1196).

In summary, hyperkalemia is a proven risk factor for adverse cardiacevents, including arrhythmias and death. Hyperkalemia has multiplecausalities, the most common of which is chronic or end-stage kidneydisease (CKD; ESRD); however, patients with T2DM and CVD are also atrisk for hyperkalemia, especially if CKD is present as a comorbidity.Treatment of these conditions with commonly prescribed agents, includingRAAS inhibitors, can exacerbate hyperkalemia, which often leads todosing limitations of these otherwise proven beneficial agents. There istherefore a clear need for a potassium control regimen to not onlycontrol serum K in the CKD/ESRD population, but also permit theadministration of therapeutic doses of cardio-protective RAAS inhibitortherapy.

Dietary intervention is one possible point of control for managingpotassium burden, but is difficult to manage. Furthermore, in thepatient population susceptible to hyperkalemia, dietary modificationsoften involve an emphasis on sodium restriction, and some patientsswitch to salt substitutes, not realizing that these can containpotassium salts (Kovesdy, Nat. Rev. Nephrol. 2014). Finally,“heart-healthy” diets are inherently rich in potassium. Ingestedpotassium is also readily bioavailable, and rapidly partitions intoextracellular fluid. For example, the typical daily potassium intake inhealthy individuals in the United States is approximately 70 mmol/d, or˜1 mmol/kg of body weight for a 70 kg individual (Holbrook, J. T., etal., Am. J. of Clin. Nutrition. 1984, 40, 786-793). Since absorption ofingested potassium from the gut into the extracellular fluid is nearlycomplete, and assuming ˜17 l of extracellular fluid in a 70 kg adult,this potassium burden would essentially double serum K (70 mmol/17 L=˜4mmol/L increase). Such an increase would be lethal in the absence ofcompensatory mechanisms, and the fact that ESRD patients on dialysis donot die during the interdialytic interval is a testament to theintegrity of the extrarenal potassium disposal mechanisms that getupregulated in ESRD (Ahmed, Seminars in Dialysis 2001). Patients withnormal renal function eliminate ˜5-10% of their daily potassium loadthrough the gut (feces). In patients with chronic renal failure, fecalexcretion can account for as much as 25% of daily potassium elimination.This adaptation is mediated by increased colonic secretion, which is 2-to 3-fold higher in dialysis patients than in normal volunteers (Sandle,G. I. and McGlone, F., Pflugers Arch 1987, 410, 173-180). This increasein fecal excretion appears due to the upregulation of the amount andlocation of so-called “big potassium” channels (BK channels; KCNMA1)present in the colonic epithelia cells, as well as an alteration in theregulatory signals that promote potassium secretion through thesechannels (Sandle, G. I. and Hunter, M. Q., J Med 2010, 103, 85-89;Sorensen, M. V. Pflugers Arch—Eur J. Physiol 2011, 462, 745-752).Additional compensation is also provided by cellular uptake of potassium(Tzamaloukas, A. H. and Avasthi, P. S., Am. J. Nephrol. 1987, 7,101-109). Despite these compensatory mechanisms, ˜15-20% of the ingestedpotassium accumulates in the extracellular space and must be removed bydialysis. Interdialytic increases that occur over the weekend can leadto serious cardiovascular events, including sudden death. In summary,dietary intervention is both impractical and insufficient.

Serum potassium can be lowered by two general mechanisms: the first isby shifting potassium intracellularly using agents such as insulin,albuterol or sodium bicarbonate (Fordjour, Am. J. Med. Sci. 2014). Thesecond is by excreting it from the body using 1 of 4 routes: the stoolwith K binding resins such as sodium polystyrene sulfonate (Na-PSS), theurine with diuretics, the blood with hemodialysis or the peritonealfluid with peritoneal dialysis (Fordjour, Am. J. Med. Sci. 2014). Otherthan Na-PSS, the medications that treat hyperkalemia, such as insulin,diuretics, beta agonists and sodium bicarbonate, simply causehypokalemia as a side effect and are not suitable as chronic treatments.Definitive therapy necessitates the removal of potassium from the body.Studies have confirmed that reducing serum potassium levels inhyperkalemia patients actually reduces the mortality risk, furthersolidifying the role of excess potassium in the risk of death. One studyfound that treatment of hyperkalemia with common therapies both improvedserum potassium levels and resulted in a statistically significantincrease in survival (An, Critical Care 2012). Another study, inhospitalized patients receiving critical care, showed that the reductionof serum potassium by ≧1 mEq/L 48 hours after hospitalization alsodecreased the mortality risk (McMahon, G. M., et al., Intensive CareMed, 2012, 38, 1834-1842). These studies suggest that treatinghyperkalemia in the acute and chronic settings can have a real impact onpatient outcomes by reducing the risk of death

The potassium binder sodium polystyrene sulfonate (Na-PSS; Kayexalate)is the most common agent used in the management of hyperkalemia inhospitalized patients (Fordjour, Am. J. Med. Sci. 2014). Polystyrenesulfonate (PSS) is typically provided as a sodium salt (Na-PSS), and inthe lumen of the intestine it exchanges sodium for secreted potassium.Most of this takes place in the colon, the site of most potassiumsecretion in the gut (and the region where K secretion appears to beupregulated in CKD). Each gram of Na-PSS can theoretically bind ˜4 mEqof cation; however, approximately 0.65 mmol of potassium is sequesteredin vivo due to competing cations (e.g., hydrogen ion, sodium, calciumand magnesium). Sodium is concomitantly released. This may lead tosodium retention, which can lead to hypernatremia, edema, and possibleworsening of hypertension or acute HF (Chernin, G. et al., Clin.Cardiol. 2012, 35(1), 32-36).

Na-PSS was approved in 1958 by the US FDA, as a potassium-binding resinin the colon for the management of hyperkalemia. This approval was basedon a clinical trial performed in 32 hyperkalemic patients, who showed adecrease in serum potassium of 0.9 mmol/l in the first 24 h followingtreatment with Na-PSS (Scherr, L. et al., NEJM 1961, 264(3), 115-119).Such acute use of Na-PSS has become common. For example, the use ofpotassium-binding resins has proven to be of value in the pre-dialysisCKD setting and in the management of emergency hyperkalemia, and isreportedly used in >95% of hyperkalemic episodes in the hospital setting(Fordjour, Am. J. Med. Sci. 2014). Na-PSS can be given orally orrectally. When given orally, it is commonly administered with sorbitolto promote diarrhea/prevent constipation. The onset of action is within1-2 h and lasts approximately 4-6 hours. The recommended average dailydose is 15-60 g given singly or in divided doses (Kessler, C. et al., J.Hosp. Med 2011, 6(3), 136-140). Kayexalate has been shown to be activein broad populations of hyperkalemic patients, including subjects bothwith and without chronic kidney disease (Fordjour, Am. J. Med. Sci.2014).

There are fewer reports of the use of Na-PSS in chronic hyperkalemia,but chronic treatment is not uncommon. Chernin et al. report aretrospective study of patients on RAAS inhibition therapy that weretreated chronically with Na-PSS as a secondary prevention ofhyperkalemia (Chernin, Clin. Cardiol. 2012). Each patient began chronictreatment after being first treated for an acute episode of hyperkalemia(K⁺ levels ≧6.0 mmol/L). Fourteen patients were treated with low-doseNa-PSS (15 g once-daily) for a total of 289 months, and this regimen wasfound to be safe and effective. No episodes of hyperkalemia wererecorded while patients were on therapy, but two subjects experiencedhypokalemia which resolved when the dose of Na-PSS was reduced. Last,none of the patients developed colonic necrosis or any otherlife-threatening event that could be attributed to Na-PSS use (Chernin,Clin. Cardiol. 2012). Chronic treatment with once-daily Na-PSS was foundsafe and effective in this study.

While Na-PSS is the current standard of care treatment for potassiumreduction in the U.S., the calcium salt of PSS (Ca-PSS) is also commonlyused in other parts of the world, including Europe (e.g., Resonium) andJapan. All salt forms of these polymers are poorly tolerated by patientsdue to a number of compliance-limiting properties, including both GIside effects such as constipation, as well as dosing complexities due todosing size and frequency, taste and/or texture which contribute to anoverall low palatability. The safety and efficacy of PSS has beenunderexplored (by modern standards) in randomized and controlledclinical trials.

Kayexalate/Na-PSS is also poorly tolerated causing a high incidence ofGI side effects including nausea, vomiting, constipation and diarrhea.In addition, Kayexalate is a milled product and consists of irregularlyshaped particles ranging in size from about 1-150 μm in size, and hassand-like properties in the human mouth: on ingestion, it gives a strongsensation of foreign matter on the palate and this sensation contributesnegatively to patient compliance (Schroder, C. H., Eur. J. Pediatr.1993, 152, 263-264). In total, the physical properties and associatedside-effects of Kayexalate lead to poor compliance and render the drugsuboptimal for chronic use. Due to these properties, there has been along felt need to provide an optimal drug for chronic use.

In summary, hyperkalemia is a serious medical condition that can lead tolife-threatening arrhythmias and sudden death. Individuals with CKD areat particular risk; however, hyperkalemia can be a comorbidity forindividuals with T2DM and CVD, and can also be exacerbated by commonmedications, especially RAAS inhibitors. The management of hyperkalemiainvolves the treatment of both acute and chronic increases in serum K⁺.For example, in an emergency medicine environment, patients can presentwith significant increases in serum K⁺ due to comorbidities that causean acute impairment in the renal excretion of potassium. Examples ofchronic hyperkalemia include the recurrent elevations in serum K⁺ thatcan occur during the interdialytic interval for patients with ESRD, orthe persistent elevations in serum K⁺ that can occur in CKD patientstaking dual RAAS blockade. There is thus a clear need for agents thatcan be used to treat hyperkalemia. Such agents, suitable for treatmentof both acute and chronic hyperkalemia, while being palatable andwell-tolerated by the patient, would be advantageous.

SUMMARY OF THE INVENTION

The present invention solves these problems by providing a polymericbinder or a composition containing a polymeric binder than can be givenonce, twice or three times a day, possesses equivalent or significantlybetter efficacy, and has physical properties that include a sphericalmorphology, smaller and more uniform particle size distribution andsignificantly improved texture-factors that contribute dramatically toimproved palatability. These improvements in efficacy (potentially lowerdoses and/or less frequent dosing) and palatability (better mouth feel,taste, etc.) should increase tolerance, which will improve patientcompliance, and hence potassium binding effectiveness.

The cation exchange polymers with low levels of crosslinking describedin this invention generally have a higher efficacy for potassium in vivothan resins such as Kayexalate. Surprisingly, approximately 1.4- to1.5-fold more potassium is excreted fecally than is achieved when, forexample, Resonium, with a high level of crosslinking, is similarly dosed(same dosing and fecal collection conditions). The higher potassiumcapacity of the polymers of this invention may enable the administrationof a lower dose of the polymer and meet the long felt need to provide anoptimal drug for chronic use in treating hyperkalemia.

In brief, the present invention is directed to compositions and methodsfor removing potassium from the gastrointestinal track, includingmethods for treating hyperkalemia, by administration of crosslinkedcation exchange polymers with a low level of crosslinking, and aspherical and better controlled particle size distribution, for improvedpatient tolerance and compliance.

A first aspect of the invention relates to a calcium salt of acrosslinked potassium binding polymer having the structure of Formula(I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and

the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%.

Another aspect of the invention relates to a calcium salt of acrosslinked potassium binding polymer having the structure of Formula(I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and

the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 5μm to about 130 μm and wherein the crosslinked potassium binding polymeris characterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.

Another aspect of the invention relates to a calcium salt of acrosslinked potassium binding polymer having the structure of Formula(I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and

the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 25μm to about 125 μm and wherein the crosslinked potassium binding polymeris characterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.

Another aspect of the invention relates to a calcium salt of acrosslinked potassium binding polymer having the structure of Formula(I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and

the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 5μm to about 70 μm and wherein the crosslinked potassium binding polymeris characterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.

Another aspect of the invention relates to a calcium salt of acrosslinked potassium binding polymer having the structure of Formula(I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and

the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 20μm to about 130 μm, wherein the potassium binding polymer has a MouthFeel score greater than 3.5, and wherein the crosslinked potassiumbinding polymer is characterized by a crosslinking of about 1.8%,wherein the term about means±10%.

Another aspect of the invention relates to a calcium salt of acrosslinked potassium binding polymer having the structure of Formula(I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and

the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 5μm to about 70 μm, wherein the potassium binding polymer has a MouthFeel score greater than 3.5, and wherein the crosslinked potassiumbinding polymer is characterized by a crosslinking of about 1.8%,wherein the term about means±10%.

Another aspect of the invention relates to a calcium salt of acrosslinked potassium binding polymer having the structure of Formula(I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,—S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is H;

each X is either absent or substituted or unsubstituted (C₆-C₁₈)aryl;

each Y is independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and the mole ratio of m to n is from about120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 20μm to about 130 μm and wherein the crosslinked potassium binding polymeris characterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.

Another aspect of the invention relates to a calcium salt of acrosslinked potassium binding polymer having the structure of Formula(I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,—S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is H;

each X is either absent or substituted or unsubstituted (C₆-C₁₈)aryl;

each Y is independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and

the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 5μm to about 70 μm and wherein the crosslinked potassium binding polymeris characterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a crosslinked potassium binding polymer of Formula (I) and apharmaceutically acceptable carrier, diluent, or excipient.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a calcium salt of a crosslinked potassium binding polymerthat has a potassium exchange capacity from about 1 mEq to about 4 mEqper gram of potassium binding polymer and a pharmaceutically acceptablecarrier, diluent, or excipient, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 8 grams of water per gram of polymerand a crosslinking of less than 5% and wherein the polymer comprisessubstantially spherical particles and is substantially endotoxin free.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a calcium salt of a crosslinked potassium binding polymerthat has a potassium exchange capacity from about 1 mEq to about 4 mEqper gram of potassium binding polymer and a pharmaceutically acceptablecarrier, diluent, or excipient, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 8 grams of water per gram of polymerand a crosslinking of less than 5%.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a calcium salt of a crosslinked potassium binding polymerthat has a potassium exchange capacity from about 1 mEq to about 4 mEqper gram of potassium binding polymer and a pharmaceutically acceptablecarrier, diluent, or excipient, wherein the potassium binding polymer ischaracterized by a crosslinking of less than 5% and a swelling ratio inwater of between about 3 grams of water per gram of polymer to about 8grams of water per gram of polymer.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a calcium salt of a crosslinked potassium binding polymerthat has a potassium exchange capacity from about 1 mEq to about 4 mEqper gram of potassium binding polymer and a pharmaceutically acceptablecarrier, diluent, or excipient, wherein the potassium binding polymer ischaracterized by a crosslinking of less than 5% and wherein mediandiameter is from about 1 μm to about 130 μm when said particles are intheir calcium salt form and swollen in water.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a calcium salt of a crosslinked potassium binding polymer anda pharmaceutically acceptable carrier, diluent, or excipient, whereinthe crosslinked potassium binding polymer is characterized by acrosslinking of less than 5% and wherein median diameter is from about 1μm to about 130 μm when said particles are in their calcium salt formand swollen in water.

Another aspect of the invention relates to a method for removingpotassium from the gastrointestinal tract of a patient showing clinicalsigns of hyperkalemia or suspected of having hyperkalemia. The methodcomprises administering a calcium salt of a crosslinked potassiumbinding polymer, or salt thereof, to the patient, wherein the potassiumbinding polymer comprises at least one monomer and one crosslinker, thecrosslinker comprising from about 1 mole % to about 3 mole % of thepotassium binding polymer and wherein the potassium binding polymer ischaracterized by a crosslinking of less than 5%.

Another aspect of the invention relates to a method for removingpotassium from the gastrointestinal tract of a patient showing clinicalsigns of hyperkalemia or suspected of having hyperkalemia. The methodcomprises administering a calcium salt of a crosslinked potassiumbinding polymer, or salt thereof, to the patient, wherein the potassiumbinding polymer comprises at least one monomer and one crosslinker,wherein the potassium binding polymer comprises substantially sphericalparticles having a median diameter from about 1 μm to about 25 μm, andwherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%.

Another aspect of the invention relates to a method for removingpotassium from the gastrointestinal tract of a patient showing clinicalsigns of hyperkalemia or suspected of having hyperkalemia. The methodcomprises administering of a calcium salt of a potassium bindingpolymer, or salt thereof, to the patient, wherein the crosslinkedpotassium binding polymer has a structure of Formula (I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆) alkyl, substituted or unsubstituted(C₆-C₁₈) aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and

the mole ratio of m to n is from about 120:1 to about 40:1;

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%.

Another aspect of the invention relates to a method for removingpotassium from the gastrointestinal tract of a patient showing clinicalsigns of hyperkalemia or suspected of having hyperkalemia is provided,the method comprising administering a calcium salt of crosslinkedpotassium binding polymer, or salt thereof, to the patient, wherein thecrosslinked potassium binding polymer comprises at least one monomer andone crosslinker, the crosslinker comprising from about 1 wt. % to about3 wt. % of the potassium binding polymer. In some embodiments, thecrosslinker comprises from about 1 mole % to about 4 mole % of thepotassium binding polymer.

Another aspect of the invention relates to a method for removingpotassium from the gastrointestinal tract of a patient showing clinicalsigns of hyperkalemia or suspected of having hyperkalemia is provided,the method comprising administering a calcium salt of crosslinkedpotassium binding polymer, or salt thereof, to the patient, wherein thepotassium binding polymer comprises substantially spherical particleshaving a median diameter from about 1 μm to about 200 μm.

Another aspect of the invention relates to a method for removingpotassium from the gastrointestinal tract of a patient showing clinicalsigns of hyperkalemia or suspected of having hyperkalemia is provided,the method comprising administering a calcium salt of crosslinkedpotassium binding polymer, or salt thereof, to the patient, wherein thecrosslinked potassium binding polymer has a structure of Formula (I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is a divalent group; and

the ratio of m to n is from about 120:1 to about 40:1

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%.

Another aspect of the invention relates to a calcium salt of crosslinkedpotassium binding polymer having the structure of Formula (I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is a divalent group; and

the ratio of m to n is from about 120:1 to about 40:1;

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a calcium salt of crosslinked potassium binding polymerhaving the structure of Formula (I):

and pharmaceutically acceptable salts thereof,

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is a divalent group; and

the ratio of m to n is from about 120:1 to about 40:1;

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%; and

a pharmaceutically acceptable carrier, diluent, or excipient.

Another aspect of the invention relates to a calcium salt of crosslinkedpotassium binding polymer having the following structure:

and pharmaceutically acceptable salts thereof,

wherein the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%.

Another aspect of the invention relates to a pharmaceutical compositioncomprising:

i) about 86.5% to about 91% of a calcium salt of a crosslinked potassiumbinding polymer having the following structure:

and pharmaceutically acceptable salts thereof,

wherein the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%;

ii) about 2.0% to about 3.0% of calcium citrate tetrahydrate;

iii) about 2.0% to about 3.0% of anhydrous citric acid;

iv) about 0.1% to about 1.0% of sucralose;

v) about 2.0% to about 3.0% of artificial orange flavored powder; and

vi) about 2.5% to about 3.5% of methyl cellulose A4C.

Another aspect of the invention relates to a pharmaceutical compositioncomprising:

i) about 86.5% to about 91% of a calcium salt of a crosslinked potassiumbinding polymer of Formula (I) and pharmaceutically acceptable saltsthereof;

ii) about 2.0% to about 3.0% of calcium citrate tetrahydrate;

iii) about 2.0% to about 3.0% of anhydrous citric acid;

iv) about 0.1% to about 1% of sucralose;

v) about 2.0% to about 3.0% of artificial orange flavored powder; and

vi) about 2.5% to about 3.5% of methyl cellulose A4C.

Another aspect of the invention relates to a pharmaceutical compositioncomprising:

i) about 89% to about 94.5% of a calcium salt of a crosslinked potassiumbinding polymer having the following structure:

and pharmaceutically acceptable salts thereof,

wherein the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%;

ii) about 0.6% to about 1.6% of calcium citrate tetrahydrate;

iii) about 0.02% to about 0.5% of anhydrous citric acid;

iv) about 0.1% to about 1% of sucralose;

v) about 0.6% to about 1.6% of vanillin powder;

vi) about 2.5% to about 3.5% of methyl cellulose A4C; and

vii) about 1.6% to about 2.6% of titanium dioxide.

Another aspect of the invention relates to a pharmaceutical compositioncomprising:

i) about 89% to about 94.5% of a calcium salt of a crosslinked potassiumbinding polymer of Formula (I) and pharmaceutically acceptable saltsthereof;

ii) about 0.6% to about 1.6% of calcium citrate tetrahydrate;

iii) about 0.02% to about 0.5% of anhydrous citric acid;

iv) about 0.1% to about 1% of sucralose;

v) about 0.6% to about 1.6% of vanillin powder;

vi) about 2.5% to about 3.5% of methyl cellulose A4C; and

vii) about 1.6% to about 2.6% of titanium dioxide.

Another aspect of the invention relates to a pharmaceutical compositioncomprising:

i) about 10% to about 26% of a calcium salt of a crosslinked potassiumbinding polymer having the following structure:

and pharmaceutically acceptable salts thereof,

wherein the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%;

ii) about 0.1% to about 1.0% of calcium citrate tetrahydrate;

iii) about 0.015% to about 0.15% of benzoic acid;

iv) about 0.1% to about 1% of anhydrous citric acid;

v) about 0.015% to about 0.15% of sucralose;

vi) about 0.1% to about 1.0% of natural orange WONF FV7466;

vii) about 0.1% to about 1.0% of xanthan gum cp; and

viii) about 73.7% to about 85.57% of water.

Another aspect of the invention relates to a pharmaceutical compositioncomprising:

i) about 10% to about 26% of a calcium salt of a crosslinked potassiumbinding polymer of Formula (I) and pharmaceutically acceptable saltsthereof;

ii) about 0.1% to about 1.0% of calcium citrate tetrahydrate;

iii) about 0.015% to about 0.15% of benzoic acid;

iv) about 0.1% to about 1% of anhydrous citric acid;

v) about 0.015% to about 0.15% of sucralose;

vi) about 0.1% to about 1.0% of natural orange WONF FV7466;

vii) about 0.1% to about 1.0% of xanthan gum cp; and

viii) about 73.7% to about 85.57% of water.

Another aspect of the invention relates to a pharmaceutical compositioncomprising:

i) about 10% to about 26% of a calcium salt of a crosslinked potassiumbinding polymer having the following structure:

and pharmaceutically acceptable salts thereof,

wherein the mole ratio of m to n is from about 120:1 to about 40:1; and

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%;

ii) about 0.01% to about 0.5% of calcium citrate tetrahydrate;

iii) about 0.01% to about 0.1% of sorbic acid;

iv) about 0.001% to about 0.1% of anhydrous citric acid;

v) about 0.05% to about 0.15% of sucralose;

vi) about 0.1% to about 1.0% of SuperVan art vanilla VM36;

vii) about 0.1% to about 1.0% of xanthan gum cp;

viii) about 0.1% to about 1.0% of titanium dioxide; and

ix) about 73.2% to about 86.65% of water.

Another aspect of the invention relates to a pharmaceutical compositioncomprising:

i) about 10% to about 26% of a calcium salt of a crosslinked potassiumbinding polymer of Formula (I) and pharmaceutically acceptable saltsthereof;

ii) about 0.01% to about 0.5% of calcium citrate tetrahydrate;

iii) about 0.01% to about 0.1% of sorbic acid;

iv) about 0.001% to about 0.1% of anhydrous citric acid;

v) about 0.05% to about 0.15% of sucralose;

vi) about 0.1% to about 1.0% of SuperVan art vanilla VM36;

vii) about 0.1% to about 1.0% of xanthan gum cp;

viii) about 0.1% to about 1.0% of titanium dioxide; and

ix) about 73.2% to about 86.65% of water.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: shows the swelling ratio of calcium polystyrene sulfonate resinsin water as well as the observed fecal potassium excretion from rodentsorally dosed with selected resins.

FIG. 2: shows the fecal K⁺ excretion of rats dosed with Ca-PSS polymerswith differing levels of crosslinking (2%, 4% and 8% DVB crosslinking)blended into chow at 4% or 8% wt/wt. The highest fecal K⁺ was seen inthe group that was fed a 2% DVB crosslinked polymer, when said polymerwas present at 8% wt/wt in chow.

FIG. 3: shows the fecal K⁺ excretion of mice dosed with Ca-PSS polymerswith differing levels of crosslinking (2%, 4% and 8% DVB crosslinking)blended into chow at 8% wt/wt. The highest fecal K⁺ was seen in thegroup that was fed a 2% DVB crosslinked polymer.

FIG. 4: shows the fecal K⁺ excretion of mice dosed with Ca-PSS polymerswith differing levels of crosslinking (1.6%, 1.8%, 2%, and 8% DVBcrosslinking) blended into chow at 8% wt/wt. The level of K⁺ in thefeces was significantly higher with 1.6%, 1.8% and 2% DVB (Examples 9,10, and 4) compared to the vehicle or 8% DVB (Example 6).

FIG. 5: shows the fecal K⁺ excretion of mice dosed with Na-PSS, USP,Ca-PSS, BP and Example 10, all blended into chow at 8% wt/wt compared toa vehicle control. Only Ca-PSS, BP and Example 10 afforded significantlevels of fecal K⁺ excretion, and the highest fecal K⁺ was seen in thegroup that was fed Example 10.

FIG. 6: shows the fecal K⁺ excretion of mice dosed with Na-PSS, USP andExample 10, both blended into chow at 4% and 8% wt/wt, and compared to avehicle control. The level of K⁺ in the feces was significantly higherwith Example 10, when present in chow at either 4% or 8% wt/wt, comparedto vehicle. Na-PSS, USP afforded significant fecal K⁺ excretion onlywhen present in chow at 8% wt/wt. The highest fecal K⁺ was seen in thegroup that was fed Example 10.

FIG. 7: shows dose-response data for mice fed Example 10 blended intochow at 2%, 4%, 6% and 8%, wt/wt, compared to a vehicle control. Thelevel of K⁺ in the feces was significantly higher for Example 10 whenpresent in chow at 4%, 6% and 8%, wt/wt, while 2% in chow afforded atrend but was not significant. Increasing amounts of Example 10 blendedin chow afford increasing amounts of K⁺ in the feces.

FIG. 8: shows fecal K⁺ excretion of mice dosed with several Examplesfrom the invention, blended in chow at 8%, wt/wt, and compared toExample 6 as a control. Examples 10, 13 and 18 afforded significantamounts of K⁺ in the feces.

FIG. 9: shows fecal K⁺ secretion of mice dosed with two Examples fromthe invention, blended in chow at 8%, wt/wt, and compared to Ca-PSS, BPas a control. Example 20 afforded the highest level of fecal potassiumin this experiment.

FIG. 10: shows scanning electron micrograph (SEM) images for Na-PSS,USP, Ca-PSS, USP, Example 13 and Example 10.

FIG. 11: shows particle size analysis data (laser diffraction) forsamples of Na-PSS, USP and Ca-PSS, BP obtained from several differentmanufacturers compared to Example 10 of the present invention.

FIG. 12: shows the relationship between DVB weight percent, DVB molepercent, and styrene:DVB ratio for crosslinked polystyrene.

FIG. 13: shows the fecal and urinary excretion of phosphate in micetreated with Example 10 compared to Na-PSS, USP as a control.

FIG. 14: shows the fecal K⁺ excretion in mice treated with Examples 30and 31 compared to Na-PSS, USP and Ca-PSS, BP as controls.

FIG. 15: shows the fecal and urinary K⁺ excretion in mice treated withExamples 32 and 33 compared to Na-PSS, USP as a control and vehicle.

FIG. 16: shows the fecal excretion of phosphate and urinary excretion ofsodium in mice treated with Examples 32 and 33 compared to Na-PSS, USPas a control and vehicle.

FIG. 17: shows the fecal K⁺ excretion of mice dosed with Examples 36,37, 38 and 34 compared to Na-PSS, USP as a control.

DETAILED DESCRIPTION OF THE INVENTION

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

Throughout this disclosure, various patents, patent applications andpublications are referenced. The disclosures of these patents, patentapplications and publications in their entireties are incorporated intothis disclosure by reference in order to more fully describe the stateof the art as known to those skilled therein as of the date of thisdisclosure. This disclosure will govern in the instance that there isany inconsistency between the patents, patent applications andpublications and this disclosure.

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. The initial definition provided for a group or termprovided in this disclosure applies to that group or term throughout thepresent disclosure individually or as part of another group, unlessotherwise indicated.

A first aspect of the invention relates to a calcium salt of acrosslinked potassium binding polymer having the structure of Formula(I):

and pharmaceutically acceptable salts thereof,

wherein:

R₁, R₂, R₃, X, Y, m, and n are as defined above; and

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%.

In some embodiments, R₁ is selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, or —S(O)₂OH. In another embodiment, R₁ is H and —S(O)₂OH.

In some embodiments, R₂ is selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, or —S(O)₂OH. In another embodiment, R₂ is H or —S(O)₂OH.

In some embodiments, R₃ is selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, and —S(O)₂OH. In another embodiment, R₃ is Hor phenyl. In yet another embodiment, R₃ is H.

In some embodiments, X is either absent. In another embodiment, X isselected from the group consisting of substituted or unsubstituted(C₁-C₆)alkyl and substituted or unsubstituted (C₆-C₁₈)aryl. In yetanother embodiment, X is absent or substituted or unsubstituted(C₆-C₁₈)aryl. In yet another embodiment, X is absent or unsubstituted(C₆-C₁₈)aryl. In another embodiment, X is absent or phenyl. In yetanother embodiment, X is absent and R₁ is H when XR₁ is attached to thecarbon atom substituted with Y.

In some embodiments, Y is selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl. In another embodiment, Y is substituted orunsubstituted (C₆-C₁₈)aryl. In another embodiment, Y is unsubstituted(C₆-C₁₈)aryl. In yet another embodiment, Y is phenyl.

In some embodiments, the mole ratio of m to n is from about 120:1 toabout 40:1. In another embodiment, the ratio of m to n is from about70:1 to about 50:1. In yet another embodiment, the ratio of m to n isfrom about 70:1 to about 60:1. In another embodiment, the ratio of m ton is about 68:1.

In some embodiments, the polymer is a styrene polymer. In anotherembodiment, the polymer is crosslinked with divinyl benzene. In yetanother embodiment, the divinyl benzene is divinyl benzene sulfonate. Inanother embodiment, the polymer is a salt of crosslinked polystyrenesulfonate. In yet another embodiment, the composition is furthersubstantially active as a phosphate binder. In another embodiment, thepatient is experiencing hyperkalemia. In yet another embodiment, thepolymer has a capacity to increase fecal phosphorous output in asubject. In another embodiment, the polymer has a capacity to decreaseurinary phosphorous output in a subject.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising a calcium salt of a crosslinked potassium bindingpolymer that has a potassium exchange capacity from about 1 mEq to about4 mEq per gram of potassium binding polymer and a pharmaceuticallyacceptable carrier, diluent, or excipient, wherein the potassium bindingpolymer is characterized by a swelling ratio in water of between about 3grams of water per gram of polymer to about 8 grams of water per gram ofpolymer and a crosslinking of less than 5% and wherein the polymercomprises substantially spherical particles and is substantiallyendotoxin free. In some embodiments, the polymer is a styrene polymer.In another embodiment, the polymer is crosslinked with divinyl benzene.In yet another embodiment, the divinyl benzene is divinyl benzenesulfonate. In another embodiment, the polymer is a salt of crosslinkedpolystyrene sulfonate. In yet another embodiment, the composition isfurther substantially active as a phosphate binder. In anotherembodiment, the patient is experiencing hyperkalemia. In yet anotherembodiment, the polymer has a capacity to increase fecal phosphorousoutput in a subject. In another embodiment, the polymer has a capacityto decrease urinary phosphorous output in a subject.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a calcium salt of a crosslinked potassium binding polymerthat has a potassium exchange capacity from about 1 mEq to about 4 mEqper gram of potassium binding polymer and a pharmaceutically acceptablecarrier, diluent, or excipient, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 8 grams of water per gram of polymerand a crosslinking of less than 5%. In some embodiments, the polymer isa styrene polymer. In another embodiment, the polymer is crosslinkedwith divinyl benzene. In yet another embodiment, the divinyl benzene isdivinyl benzene sulfonate. In another embodiment, the polymer is a saltof crosslinked polystyrene sulfonate. In yet another embodiment, thecomposition is further substantially active as a phosphate binder. Inanother embodiment, the patient is experiencing hyperkalemia. In yetanother embodiment, the polymer has a capacity to increase fecalphosphorous output in a subject. In another embodiment, the polymer hasa capacity to decrease urinary phosphorous output in a subject.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising a calcium salt of a crosslinked potassium bindingpolymer that has a potassium exchange capacity from about 1 mEq to about4 mEq per gram of potassium binding polymer and a pharmaceuticallyacceptable carrier, diluent, or excipient, wherein the potassium bindingpolymer is characterized by a crosslinking of less than 5% and aswelling ratio in water of between about 3 grams of water per gram ofpolymer to about 8 grams of water per gram of polymer. In someembodiments, the polymer is a styrene polymer. In another embodiment,the polymer is crosslinked with divinyl benzene. In yet anotherembodiment, the divinyl benzene is divinyl benzene sulfonate. In anotherembodiment, the polymer is a salt of crosslinked polystyrene sulfonate.In yet another embodiment, the composition is further substantiallyactive as a phosphate binder. In another embodiment, the patient isexperiencing hyperkalemia. In yet another embodiment, the polymer has acapacity to increase fecal phosphorous output in a subject. In anotherembodiment, the polymer has a capacity to decrease urinary phosphorousoutput in a subject.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a calcium salt of a crosslinked potassium binding polymerthat has a potassium exchange capacity from about 1 mEq to about 4 mEqper gram of potassium binding polymer and a pharmaceutically acceptablecarrier, diluent, or excipient, wherein the potassium binding polymer ischaracterized by a crosslinking of less than 5% and wherein mediandiameter is from about 1 μm to about 130 μm when said particles are intheir calcium salt form and swollen in water. In some embodiments, thepolymer is a styrene polymer. In another embodiment, the polymer iscrosslinked with divinyl benzene. In yet another embodiment, the divinylbenzene is divinyl benzene sulfonate. In another embodiment, the polymeris a salt of crosslinked polystyrene sulfonate. In yet anotherembodiment, the composition is further substantially active as aphosphate binder. In another embodiment, the patient is experiencinghyperkalemia. In yet another embodiment, the polymer has a capacity toincrease fecal phosphorous output in a subject. In another embodiment,the polymer has a capacity to decrease urinary phosphorous output in asubject.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising a calcium salt of a crosslinked potassium bindingpolymer and a pharmaceutically acceptable carrier, diluent, orexcipient, wherein the crosslinked potassium binding polymer ischaracterized by a crosslinking of less than 5% and wherein mediandiameter is from about 1 μm to about 130 μm when said particles are intheir calcium salt form and swollen in water. In some embodiments, thepolymer is a styrene polymer. In another embodiment, the polymer iscrosslinked with divinyl benzene. In yet another embodiment, the divinylbenzene is divinyl benzene sulfonate. In another embodiment, the polymeris a salt of crosslinked polystyrene sulfonate. In yet anotherembodiment, the composition is further substantially active as aphosphate binder. In another embodiment, the patient is experiencinghyperkalemia. In yet another embodiment, the polymer has a capacity toincrease fecal phosphorous output in a subject. In another embodiment,the polymer has a capacity to decrease urinary phosphorous output in asubject.

Another aspect of the invention relates to a composition for removingpotassium from the gastrointestinal tract of a patient showing clinicalsigns of hyperkalemia or suspected of having hyperkalemia, comprising acalcium salt of a potassium binding polymer, or salt thereof, to thepatient, wherein the crosslinked potassium binding polymer has astructure of Formula (I):

and pharmaceutically acceptable salts thereof

wherein:

each R₁ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆) alkyl, substituted or unsubstituted(C₆-C₁₈) aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₂ is independently selected from the group consisting of H,substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH;

each R₃ is independently selected from the group consisting of H,halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH;

each X is either absent or independently selected from the groupconsisting of substituted or unsubstituted (C₁-C₆)alkyl and substitutedor unsubstituted (C₆-C₁₈)aryl;

each Y is independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and

the mole ratio of m to n is from about 120:1 to about 40:1;

wherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%; and

a pharmaceutically acceptable carrier, diluent, or excipient.

Another aspect of the invention relates to a pharmaceutical compositioncomprising: a i) a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof;ii) calcium citrate tetrahydrate; iii) anhydrous citric acid; iv)sucralose; v) artificial orange flavored powder; and vi) methylcellulose.

In some embodiments, the pharmaceutical composition comprises about86.5% to about 91% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 87%to about 90% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about88% to about 89% of the calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 86%,about 87%, about 88%, about 89%, or about 90% of a calcium salt of acrosslinked potassium binding polymer of Formula (I) andpharmaceutically acceptable salts thereof. In yet another embodiment,the pharmaceutical composition comprises about 88.6% of a calcium saltof a crosslinked potassium binding polymer of Formula (I) andpharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutical composition comprises about 2.0%to about 3.0% of calcium citrate tetrahydrate. In another embodiment,the pharmaceutical composition comprises about 2.1% to about 2.9% ofcalcium citrate tetrahydrate. In yet another embodiment, thepharmaceutical composition comprises about 2.2% to about 2.8% of calciumcitrate tetrahydrate. In another embodiment, the pharmaceuticalcomposition comprises about 2.3% to about 2.7% of calcium citratetetrahydrate. In yet another embodiment, the pharmaceutical compositioncomprises about 2.4% to about 2.6% of calcium citrate tetrahydrate. Inanother embodiment, the pharmaceutical composition comprises about 2.5%to about 2.7% of calcium citrate tetrahydrate. In yet anotherembodiment, the pharmaceutical composition comprises about 2.0%, about2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about2.8%, about 2.9%, or about 3.0% of calcium citrate tetrahydrate. Inanother embodiment, the pharmaceutical composition comprises about 2.64%of calcium citrate tetrahydrate.

In some embodiments, the pharmaceutical composition comprises about 2.0%to about 3.0% of anhydrous citric acid. In another embodiment, thepharmaceutical composition comprises about 2.1% to about 2.9% ofanhydrous citric acid. In yet another embodiment, the pharmaceuticalcomposition comprises about 2.2% to about 2.8% of anhydrous citric acid.In another embodiment, the pharmaceutical composition comprises about2.3% to about 2.7% of anhydrous citric acid. In yet another embodiment,the pharmaceutical composition comprises about 2.4% to about 2.6% ofanhydrous citric acid. In another embodiment, the pharmaceuticalcomposition comprises about 2.5% to about 2.7% of anhydrous citric acid.In yet another embodiment, the pharmaceutical composition comprisesabout 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%,about 2.6%, about 2.7%, about 2.8%, about 2.9%, or about 3.0% ofanhydrous citric acid. In another embodiment, the pharmaceuticalcomposition comprises about 2.66% of anhydrous citric acid.

In some embodiments, the pharmaceutical composition comprises about 0.1%to about 1% of sucralose. In another embodiment, the pharmaceuticalcomposition comprises about 0.2% to about 0.9% of sucralose. In yetanother embodiment, the pharmaceutical composition comprises about 0.3%to about 0.8% of sucralose. In another embodiment, the pharmaceuticalcomposition comprises about 0.4% to about 0.8% of sucralose. In anotherembodiment, the pharmaceutical composition comprises about 0.5% to about0.7% of sucralose. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.1%, about 0.2%, about 0.3%, about 0.4%,about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about1.0% of sucralose. In another embodiment, the pharmaceutical compositioncomprises about 0.53% of sucralose.

In some embodiments, the pharmaceutical composition comprises about 2.0%to about 3.0% of artificial orange flavored powder. In anotherembodiment, the pharmaceutical composition comprises about 2.1% to about2.9% of artificial orange flavored powder. In yet another embodiment,the pharmaceutical composition comprises about 2.2% to about 2.8% ofartificial orange flavored powder. In another embodiment, thepharmaceutical composition comprises about 2.3% to about 2.7% ofartificial orange flavored powder. In yet another embodiment, thepharmaceutical composition comprises about 2.4% to about 2.6% ofartificial orange flavored powder. In another embodiment, thepharmaceutical composition comprises about 2.5% to about 2.7% ofartificial orange flavored powder. In yet another embodiment, thepharmaceutical composition comprises about 2.0%, about 2.1%, about 2.2%,about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%,about 2.9%, or about 3.0% of artificial orange flavored powder. Inanother embodiment, the pharmaceutical composition comprises about 2.66%of artificial orange flavored powder. Ine one embodiment, the artificialorange flavored powder is artificial orange flavored powder FV633.

In some embodiments, the pharmaceutical composition comprises about 2.5%to about 3.5% of methyl cellulose. In another embodiment, thepharmaceutical composition comprises about 2.6% to about 3.4% of methylcellulose. In yet another embodiment, the pharmaceutical compositioncomprises about 2.7% to about 3.3% of methyl cellulose. In anotherembodiment, the pharmaceutical composition comprises about 2.8% to about3.2% of methyl cellulose. In yet another embodiment, the pharmaceuticalcomposition comprises about 2.9% to about 3.1% of methyl cellulose. Inanother embodiment, the pharmaceutical composition comprises about 2.8%to about 3.0% of methyl cellulose. In yet another embodiment, thepharmaceutical composition comprises about 2.5%, about 2.6%, about 2.7%,about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%,about 3.4%, or about 3.5% of methyl cellulose. In yet anotherembodiment, the pharmaceutical composition comprises about 2.92% ofmethyl cellulose. In one embodiment, the methyl cellulose is methylcellulose A4C.

Another aspect of the invention relates to a pharmaceutical compositioncomprising: i) a calcium salt of a crosslinked potassium binding polymerof Formula (I) and pharmaceutically acceptable salts thereof; ii)calcium citrate tetrahydrate; iii) anhydrous citric acid; iv) sucralose;v) vanillin powder; vi) methyl cellulose; and vii) titanium dioxide.

In some embodiments, the pharmaceutical composition comprises about 89%to about 94.5% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 90%to about 93.5% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about91% to about 92.5% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 89%,about 89.5%, about 90%, about 90.5%, about 91%, about 91.5%, about 92%,about 92.5%, about 93%, about 93.5%, about 94%, about 94.5% of a calciumsalt of a crosslinked potassium binding polymer of Formula (I) andpharmaceutically acceptable salts thereof. In yet another embodiment,the pharmaceutical composition comprises about 91.7% of a calcium saltof a crosslinked potassium binding polymer of Formula (I) andpharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutical composition comprises about 0.6%to about 1.6% of calcium citrate tetrahydrate. In another embodiment,the pharmaceutical composition comprises about 0.7% to about 1.5% ofcalcium citrate tetrahydrate. In yet another embodiment, thepharmaceutical composition comprises about 0.8% to about 1.4% of calciumcitrate tetrahydrate. In another embodiment, the pharmaceuticalcomposition comprises about 0.8% to about 1.3% of calcium citratetetrahydrate. In yet another embodiment, the pharmaceutical compositioncomprises about 0.9% to about 1.2% of calcium citrate tetrahydrate. Inanother embodiment, the pharmaceutical composition comprises about 0.6%,about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%,about 1.3%, about 1.4%, about 1.5%, or about 1.6% of calcium citratetetrahydrate. In another embodiment, the pharmaceutical compositioncomprises about 1.21% of calcium citrate tetrahydrate.

In some embodiments, the pharmaceutical composition comprises about0.02% to about 0.5% of anhydrous citric acid. In another embodiment, thepharmaceutical composition comprises about 0.03% to about 0.4% ofanhydrous citric acid. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.04% to about 0.3% of anhydrous citricacid. In another embodiment, the pharmaceutical composition comprisesabout 0.05% to about 0.2% of anhydrous citric acid. In yet anotherembodiment, the pharmaceutical composition comprises about 0.1% to about0.3% of anhydrous citric acid. In another embodiment, the pharmaceuticalcomposition comprises about 0.2% to about 0.3% of anhydrous citric acid.In yet another embodiment, the pharmaceutical composition comprisesabout 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%,about 0.4%, or about 0.5% of anhydrous citric acid. In anotherembodiment, the pharmaceutical composition comprises about 0.24% ofanhydrous citric acid.

In some embodiments, the pharmaceutical composition comprises about 0.1%to about 1% of sucralose. In another embodiment, the pharmaceuticalcomposition comprises about 0.2% to about 0.9% of sucralose. In yetanother embodiment, the pharmaceutical composition comprises about 0.3%to about 0.8% of sucralose. In another embodiment, the pharmaceuticalcomposition comprises about 0.4% to about 0.7% of sucralose. In yetanother embodiment, the pharmaceutical composition comprises about 0.5%to about 0.6% of sucralose. In another embodiment, the pharmaceuticalcomposition comprises about 0.1%, about 0.2%, about 0.3%, about 0.4%,about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about1.0% of sucralose. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.55% of sucralose.

In some embodiments, the pharmaceutical composition comprises about 0.6%to about 1.6% of vanillin powder. In another embodiment, thepharmaceutical composition comprises about 0.7% to about 1.5% ofvanillin powder. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.8% to about 1.4% of vanillin powder. Inanother embodiment, the pharmaceutical composition comprises about 0.9%to about 1.3% of vanillin powder. In yet another embodiment, thepharmaceutical composition comprises about 1.0% to about 1.2% ofvanillin powder. In another embodiment, the pharmaceutical compositioncomprises about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%,about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, or about1.6% of vanillin powder.

In some embodiments, the pharmaceutical composition comprises about 2.5%to about 3.5% of methyl cellulose. In another embodiment, thepharmaceutical composition comprises about 2.6% to about 3.4% of methylcellulose. In yet another embodiment, the pharmaceutical compositioncomprises about 2.7% to about 3.3% of methyl cellulose. In anotherembodiment, the pharmaceutical composition comprises about 2.8% to about3.3% of methyl cellulose. In yet another embodiment, the pharmaceuticalcomposition comprises about 2.9% to about 3.3% of methyl cellulose. Inanother embodiment, the pharmaceutical composition comprises about 3.0%to about 3.2% of methyl cellulose. In yet another embodiment, thepharmaceutical composition comprises about 2.9% to about 3.1% of methylcellulose. In another embodiment, the pharmaceutical compositioncomprises about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%,about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, or about3.5% of methyl cellulose. In yet another embodiment, the pharmaceuticalcomposition comprises about 3.03% of methyl cellulose. In oneembodiment, the methyl cellulose is methyl cellulose A4C.

In some embodiments, the pharmaceutical composition comprises about 1.6%to about 2.6% of titanium dioxide. In another embodiment, thepharmaceutical composition comprises about 1.7% to about 2.5% oftitanium dioxide. In yet another embodiment, the pharmaceuticalcomposition comprises about 1.8% to about 2.4% of titanium dioxide. Inanother embodiment, the pharmaceutical composition comprises about 1.9%to about 2.3% of titanium dioxide. In yet another embodiment, thepharmaceutical composition comprises about 2.0% to about 2.3% oftitanium dioxide. In another embodiment, the pharmaceutical compositioncomprises about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%,about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, or about2.6% of titanium dioxide.

Another aspect of the invention relates to a pharmaceutical compositioncomprising: i) a calcium salt of a crosslinked potassium binding polymerof Formula (I) and pharmaceutically acceptable salts thereof; ii)calcium citrate tetrahydrate; iii) benzoic acid; iv) anhydrous citricacid; v) sucralose; vi) of natural orange WONF FV7466; vii) xanthan gum;and viii) water.

In some embodiments, the pharmaceutical composition comprises about 10%to about 26% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 11%to about 25% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about12% to about 24% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 13%to about 23% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about14% to about 22% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 15%to about 21% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about16% to about 20% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 15%to about 19% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about16% to about 18% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 15%to about 17% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about23%, about 24%, about 25%, or about 26% of a calcium salt of acrosslinked potassium binding polymer of Formula (I) andpharmaceutically acceptable salts thereof. In another embodiment, thepharmaceutical composition comprises about 16.28% of a calcium salt of acrosslinked potassium binding polymer of Formula (I) andpharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutical composition comprises about 0.1%to about 1.0% of calcium citrate tetrahydrate. In another embodiment,the pharmaceutical composition comprises about 0.2% to about 0.9% ofcalcium citrate tetrahydrate. In yet another embodiment, thepharmaceutical composition comprises about 0.3% to about 0.8% of calciumcitrate tetrahydrate. In another embodiment, the pharmaceuticalcomposition comprises about 0.4% to about 0.7% of calcium citratetetrahydrate. In yet another embodiment, the pharmaceutical compositioncomprises about 0.5% to about 0.6% of calcium citrate tetrahydrate. Inanother embodiment, the pharmaceutical composition comprises about 0.4%to about 0.6% of calcium citrate tetrahydrate. In yet anotherembodiment, the pharmaceutical composition comprises about 0.4% to about0.5% of calcium citrate tetrahydrate. In another embodiment, thepharmaceutical composition comprises about 0.1%, about 0.2%, about 0.3%,about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%,or about 1.0% of calcium citrate tetrahydrate. In yet anotherembodiment, the pharmaceutical composition comprises about 0.49% ofcalcium citrate tetrahydrate.

In some embodiments, the pharmaceutical composition comprises about0.015% to about 0.15% of benzoic acid. In another embodiment, thepharmaceutical composition comprises about 0.02% to about 0.12% ofbenzoic acid. In yet another embodiment, the pharmaceutical compositioncomprises about 0.03% to about 0.13% of benzoic acid. In anotherembodiment, the pharmaceutical composition comprises about 0.04% toabout 0.12% of benzoic acid. In yet another embodiment, thepharmaceutical composition comprises about 0.05% to about 0.11% ofbenzoic acid. In another embodiment, the pharmaceutical compositioncomprises about 0.06% to about 0.10% of benzoic acid. In yet anotherembodiment, the pharmaceutical composition comprises about 0.07% toabout 0.11% of benzoic acid. In another embodiment, the pharmaceuticalcomposition comprises about 0.08% to about 0.11% of benzoic acid. In yetanother embodiment, the pharmaceutical composition comprises about0.090% to about 0.11% of benzoic acid. In another embodiment, thepharmaceutical composition comprises about 0.015%, 0.02%, 0.03%, 0.04%,0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, orabout 0.15% of benzoic acid.

In some embodiments, the pharmaceutical composition comprises about 0.1%to about 1% of anhydrous citric acid. In another embodiment, thepharmaceutical composition comprises about 0.2% to about 0.9% ofanhydrous citric acid. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.3% to about 0.8% of anhydrous citric acid.In another embodiment, the pharmaceutical composition comprises about0.4% to about 0.8% of anhydrous citric acid. In yet another embodiment,the pharmaceutical composition comprises about 0.5% to about 0.7% ofanhydrous citric acid. In another embodiment, the pharmaceuticalcomposition comprises about 0.4% to about 0.6% of anhydrous citric acid.In yet another embodiment, the pharmaceutical composition comprisesabout 0.4% to about 0.5% of anhydrous citric acid. In anotherembodiment, the pharmaceutical composition comprises about 0.1%, about0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about0.8%, about 0.9%, or about 1% of anhydrous citric acid. In yet anotherembodiment, the pharmaceutical composition comprises about 0.49% ofanhydrous citric acid.

In some embodiments, the pharmaceutical composition comprises about0.015% to about 0.15% of sucralose. In another embodiment, thepharmaceutical composition comprises about 0.02% to about 0.14% ofsucralose. In yet another embodiment, the pharmaceutical compositioncomprises about 0.03% to about 0.13% of sucralose. In anotherembodiment, the pharmaceutical composition comprises about 0.04% toabout 0.12% of sucralose. In another embodiment, the pharmaceuticalcomposition comprises about 0.05% to about 0.11% of sucralose. In yetanother embodiment, the pharmaceutical composition comprises about 0.06%to about 0.10% of sucralose. In another embodiment, the pharmaceuticalcomposition comprises about 0.07% to about 0.11% of sucralose. In yetanother embodiment, the pharmaceutical composition comprises about 0.08%to about 0.11% of sucralose. In another embodiment, the pharmaceuticalcomposition comprises about 0.09% to about 0.11% of sucralose. In yetanother embodiment, the pharmaceutical composition comprises about 0.10%to about 0.11% of sucralose. In another embodiment, the pharmaceuticalcomposition comprises about 0.015%, about 0.02%, about 0.03%, about0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%,about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, orabout 0.15% of sucralose.

In some embodiments, the pharmaceutical composition comprises about 0.1%to about 1.0% of natural orange WONF FV7466. In another embodiment, thepharmaceutical composition comprises about 0.2% to about 0.9% of naturalorange WONF FV7466. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.3% to about 0.8% of natural orange WONFFV7466. In another embodiment, the pharmaceutical composition comprisesabout 0.4% to about 0.8% of natural orange WONF FV7466. In yet anotherembodiment, the pharmaceutical composition comprises about 0.5% to about0.7% of natural orange WONF FV7466. In another embodiment, thepharmaceutical composition comprises about 0.4% to about 0.6% of naturalorange WONF FV7466. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.4% to about 0.5% of natural orange WONFFV7466. In another embodiment, the pharmaceutical composition comprisesabout 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%,about 0.7%, about 0.8%, about 0.9%, or about 1% of natural orange WONFFV7466. In yet another embodiment, the pharmaceutical compositioncomprises about 0.49% of natural orange WONF FV7466.

In some embodiments, the pharmaceutical composition comprises about 0.1%to about 1.0% of xanthan gum. In another embodiment, the pharmaceuticalcomposition comprises about 0.2% to about 0.9% of xanthan gum. In yetanother embodiment, the pharmaceutical composition comprises about 0.3%to about 0.8% of xanthan gum. In another embodiment, the pharmaceuticalcomposition comprises about 0.4% to about 0.8% of xanthan gum. In yetanother embodiment, the pharmaceutical composition comprises about 0.5%to about 0.7% of xanthan gum. In another embodiment, the pharmaceuticalcomposition comprises about 0.4% to about 0.6% of xanthan gum. In yetanother embodiment, the pharmaceutical composition comprises about 0.4%to about 0.5% of xanthan gum. In another embodiment, the pharmaceuticalcomposition comprises about 0.1%, about 0.2%, about 0.3%, about 0.4%,about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1%of xanthan gum. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.68% of xanthan gum. In one embodiment, thexanthan gum is xanthan gum cp.

In some embodiments, the pharmaceutical composition comprises about73.7% to about 85.6% of water. In another embodiment, the pharmaceuticalcomposition comprises about 74% to about 84% of water. In yet anotherembodiment, the pharmaceutical composition comprises about 75% to about83% of water. In another embodiment, the pharmaceutical compositioncomprises about 76% to about 82% of water. In yet another embodiment,the pharmaceutical composition comprises about 77% to about 81% ofwater. In another embodiment, the pharmaceutical composition comprisesabout 78% to about 82% of water. In yet another embodiment, thepharmaceutical composition comprises about 79% to about 82% of water. Inanother embodiment, the pharmaceutical composition comprises about 80%to about 82% of water. In yet another embodiment, the pharmaceuticalcomposition comprises about 73.7%, about 74%, about 75%, about 76%,about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about83%, or about 84% of water. In another embodiment, the pharmaceuticalcomposition comprises about 81.4% of water.

Another aspect of the invention relates to a pharmaceutical compositioncomprising: i) a calcium salt of a crosslinked potassium binding polymerof Formula (I) and pharmaceutically acceptable salts thereof, ii)calcium citrate tetrahydrate; iii) sorbic acid; iv) anhydrous citricacid; v) sucralose; vi) SuperVan art vanilla VM36; vii) xanthan gum cp;viii) titanium dioxide; and ix) water.

In some embodiments, the pharmaceutical composition comprises about 10%to about 26% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 11%to about 25% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about12% to about 24% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 13%to about 23% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about14% to about 22% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 15%to about 21% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about16% to about 20% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 15%to about 19% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about16% to about 18% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inanother embodiment, the pharmaceutical composition comprises about 15%to about 17% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) and pharmaceutically acceptable salts thereof. Inyet another embodiment, the pharmaceutical composition comprises about10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about23%, about 24%, about 25%, or about 26% of a calcium salt of acrosslinked potassium binding polymer of Formula (I) andpharmaceutically acceptable salts thereof. In another embodiment, thepharmaceutical composition comprises about 16.36% of a calcium salt of acrosslinked potassium binding polymer of Formula (I) andpharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutical composition comprises about0.01% to about 0.5% of calcium citrate tetrahydrate. In anotherembodiment, the pharmaceutical composition comprises about 0.02% toabout 0.4% of calcium citrate tetrahydrate. In yet another embodiment,the pharmaceutical composition comprises about 0.03% to about 0.3% ofcalcium citrate tetrahydrate. In another embodiment, the pharmaceuticalcomposition comprises about 0.04% to about 0.2% of calcium citratetetrahydrate. In yet another embodiment, the pharmaceutical compositioncomprises about 0.06% to about 0.3% of calcium citrate tetrahydrate. Inanother embodiment, the pharmaceutical composition comprises about 0.07%to about 0.3% of calcium citrate tetrahydrate. In yet anotherembodiment, the pharmaceutical composition comprises about 0.08% toabout 0.3% of calcium citrate tetrahydrate. In another embodiment, thepharmaceutical composition comprises about 0.09% to about 0.3% ofcalcium citrate tetrahydrate. In yet another embodiment, thepharmaceutical composition comprises about 0.01% to about 0.3% ofcalcium citrate tetrahydrate. In another embodiment, the pharmaceuticalcomposition comprises about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%,0.07%, 0.08%, 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, orabout 0.5% of calcium citrate tetrahydrate. In yet another embodiment,the pharmaceutical composition comprises about 0.22% of calcium citratetetrahydrate.

In some embodiments, the pharmaceutical composition comprises about0.01% to about 0.1% of sorbic acid. In another embodiment, thepharmaceutical composition comprises about 0.02% to about 0.09% ofsorbic acid. In yet another embodiment, the pharmaceutical compositioncomprises about 0.03% to about 0.08% of sorbic acid. In anotherembodiment, the pharmaceutical composition comprises about 0.04% toabout 0.07% of sorbic acid. In yet another embodiment, thepharmaceutical composition comprises about 0.04% to about 0.06% ofsorbic acid. In another embodiment, the pharmaceutical compositioncomprises about 0.01%, about 0.02%, about 0.03%, about 0.04%, about0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0.1%of sorbic acid.

In some embodiments, the pharmaceutical composition comprises about0.001% to about 0.1% of anhydrous citric acid. In another embodiment,the pharmaceutical composition comprises about 0.002% to about 0.09% ofanhydrous citric acid. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.003% to about 0.08% of anhydrous citricacid. In another embodiment, the pharmaceutical composition comprisesabout 0.004% to about 0.07% of anhydrous citric acid. In yet anotherembodiment, the pharmaceutical composition comprises about 0.005% toabout 0.06% of anhydrous citric acid. In another embodiment, thepharmaceutical composition comprises about 0.006% to about 0.05% ofanhydrous citric acid. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.007% to about 0.04% of anhydrous citricacid. In another embodiment, the pharmaceutical composition comprisesabout 0.008% to about 0.03% of anhydrous citric acid. In yet anotherembodiment, the pharmaceutical composition comprises about 0.009% toabout 0.02% of anhydrous citric acid. In another embodiment, thepharmaceutical composition comprises about 0.001%, about 0.002%, about0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about0.008%, about 0.009%, about 0.01%, about 0.02%, about 0.03%, about0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%,or about 0.1% of anhydrous citric acid

In some embodiments, the pharmaceutical composition comprises about0.05% to about 0.15% of sucralose. In another embodiment, thepharmaceutical composition comprises about 0.06% to about 0.14% ofsucralose. In yet another embodiment, the pharmaceutical compositioncomprises about 0.07% to about 0.13% of sucralose. In anotherembodiment, the pharmaceutical composition comprises about 0.08% toabout 0.12% of sucralose. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.09% to about 0.11% of sucralose. Inanother embodiment, the pharmaceutical composition comprises about0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%,about 0.11%, about 0.12%, about 0.13%, or about 0.14% of sucralose.

In some embodiments, the pharmaceutical composition comprises about 0.1%to about 1.0% of SuperVan art vanilla VM36. In another embodiment, thepharmaceutical composition comprises about 0.2% to about 0.9% ofSuperVan art vanilla VM36. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.3% to about 0.8% of SuperVan art vanillaVM36. In another embodiment, the pharmaceutical composition comprisesabout 0.4% to about 0.8% of SuperVan art vanilla VM36. In yet anotherembodiment, the pharmaceutical composition comprises about 0.5% to about0.7% of SuperVan art vanilla VM36. In another embodiment, thepharmaceutical composition comprises about 0.4% to about 0.6% ofSuperVan art vanilla VM36. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.4% to about 0.5% of SuperVan art vanillaVM36. In another embodiment, the pharmaceutical composition comprisesabout 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%,about 0.7%, about 0.8%, about 0.9%, or about 1% of SuperVan art vanillaVM36. In yet another embodiment, the pharmaceutical compositioncomprises about 0.49% of SuperVan art vanilla VM36.

In some embodiments, the pharmaceutical composition comprises about 0.1%to about 1.0% of xanthan gum. In another embodiment, the pharmaceuticalcomposition comprises about 0.2% to about 0.9% of xanthan gum. In yetanother embodiment, the pharmaceutical composition comprises about 0.3%to about 0.8% of xanthan gum. In another embodiment, the pharmaceuticalcomposition comprises about 0.4% to about 0.8% of xanthan gum. In yetanother embodiment, the pharmaceutical composition comprises about 0.5%to about 0.7% of xanthan gum. In another embodiment, the pharmaceuticalcomposition comprises about 0.4% to about 0.6% of xanthan gum. In yetanother embodiment, the pharmaceutical composition comprises about 0.4%to about 0.5% of xanthan gum. In another embodiment, the pharmaceuticalcomposition comprises about 0.1%, about 0.2%, about 0.3%, about 0.4%,about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1%of xanthan gum. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.59% of xanthan gum. In one embodiment, thexanthan gum is xanthan gum cp.

In some embodiments, the pharmaceutical composition comprises about 0.1%to about 1.0% of titanium dioxide. In another embodiment, thepharmaceutical composition comprises about 0.2% to about 0.9% oftitanium dioxide. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.3% to about 0.8% of titanium dioxide. Inanother embodiment, the pharmaceutical composition comprises about 0.4%to about 0.8% of titanium dioxide. In yet another embodiment, thepharmaceutical composition comprises about 0.5% to about 0.7% oftitanium dioxide. In another embodiment, the pharmaceutical compositioncomprises about 0.3% to about 0.6% of titanium dioxide. In yet anotherembodiment, the pharmaceutical composition comprises about 0.3% to about0.5% of titanium dioxide. In another embodiment, the pharmaceuticalcomposition comprises about 0.1%, about 0.2%, about 0.3%, about 0.4%,about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1%of titanium dioxide. In yet another embodiment, the pharmaceuticalcomposition comprises about 0.39% of titanium dioxide.

In some embodiments, the pharmaceutical composition comprises about73.2% to about 86.65% water. In another embodiment, the pharmaceuticalcomposition comprises about 74% to about 86% of water. In yet anotherembodiment, the pharmaceutical composition comprises about 75% to about85% of water. In another embodiment, the pharmaceutical compositioncomprises about 76% to about 84% of water. In yet another embodiment,the pharmaceutical composition comprises about 77% to about 83% ofwater. In another embodiment, the pharmaceutical composition comprisesabout 78% to about 82% of water. In yet another embodiment, thepharmaceutical composition comprises about 79% to about 82% of water. Inanother embodiment, the pharmaceutical composition comprises about 80%to about 82% of water. In yet another embodiment, the pharmaceuticalcomposition comprises about 73.2%, about 74%, about 75%, about 76%,about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about83%, or about 84% of water. In another embodiment, the pharmaceuticalcomposition comprises about 81.8% of water.

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is, as “including, but not limited to”.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Among the various aspects of the invention are crosslinked cationexchange polymers having desirable particle size, particle shape,particle size distribution, swelling ratio, potassium binding capacity,and methods of removing potassium by administering the polymer—or apharmaceutical composition including the polymer—to an animal subject inneed thereof. Another aspect of the invention is a method for removingpotassium and/or treating hyperkalemia from an animal subject in needthereof comprising administering a potassium binding polymer to theanimal subject. The potassium binding polymer is a crosslinked cationexchange polymer comprising acid groups in their acid or salt form andin the form of substantially spherical particles having a morecontrolled particle size distribution than Kayexylate, Kalimate and thelike.

Unless particles are perfectly monodisperse, i.e., all the particleshave the same dimensions, polymer resins will typically consist of astatistical distribution of particles of different sizes. Thisdistribution of particles can be represented in several ways. Withoutbeing bound to a particular theory, it is often convenient to assessparticle size using both number weighted distributions and volumeweighted distributions. Image analysis is a counting technique and canprovide a number weighted distribution: each particle is given equalweighting irrespective of its size. Light scattering techniques such aslaser diffraction give a volume weighted distribution: the contributionof each particle in the distribution relates to the volume of thatparticle, i.e. the relative contribution will be proportional to(size)³.

When comparing particle size data for the same sample measured bydifferent techniques, it is important to realize that the types ofdistribution being measured and reported can produce very differentparticle size results. For example, for a sample consisting of equalnumbers of particles with diameters of 5 μm and 50 μm, an analyticalmethod that provides a weighted distribution would give equal weightingto both types of particles and said sample would consist of 50% 5 μmparticles and 50% 50 μm particles, by number. The same sample, analyzedusing an analytical method that provides a volume weighted distribution,would represent the 50 μm samples as present at 1000× the intensity ofthe 5 μm particles (since volume is a (radius)³ function if assuming theparticles are spheres).

For volume weighted particle size distributions, such as those measuredby laser diffraction, it is often convenient to report parameters basedupon the maximum particle size for a given percentage volume of thesample. Percentiles are defined here using the nomenclature “Dv(B)”where “D”=diameter, “v”=volume, and “B”=is percentage written as adecimal fraction. For example, when expressing particle size for a givensample as “D_(v)(0.5)=50 μm,” 50% of the sample is below this particlesize. Thus, the D_(v)(0.5) would be the maximum particle diameter belowwhich 50% of the sample volume exists—also known as the median particlesize by volume. For the scenario described earlier wherein a sampleconsists of equal numbers of particles with diameters of 5 μm and 50 μm,a volume analysis of this sample performed via laser diffraction couldtheoretically afford: D_(v)(0.999)=50 μm and D_(v)(0.001)=5 μm. Inpractice, samples are typically characterized by reporting a range ofpercentiles, typically the median, D_(v)(0.5), and values above andbelow the median (e.g., typically D_(v)(0.1) and D_(v)(0.9)).

The potassium binding polymer is a crosslinked cation exchange polymercomprising acid groups in their acid or salt form and in the form ofsubstantially spherical particles having a median diameter, when intheir calcium salt form and swollen in water, of from about 1 μm toabout 200 μm. In other embodiments, the substantially sphericalparticles have a median diameter, when in their calcium salt form andswollen in water, of about 1 μm to about 130 μm. In another embodiment,the substantially spherical particles have a median diameter, when intheir calcium salt form and swollen in water, of about 1 μm to about 60μm. In yet another embodiment, the substantially spherical particleshave a median diameter, when in their calcium salt form and swollen inwater, of about 60 μm to about 120 μm.

In some embodiments, the D_(v)50—the median particle size by volume anddefined as the maximum particle diameter below which 50% of the samplevolume exists—is between about 20 μm and about 100 μm. In yet anotherembodiment, D_(v)(0.5) is between about 60 μm and about 90 μm. Inanother embodiment, D_(v)(0.5) is between about 60 μm and about 70 μm.In another embodiment, D_(v)(0.5) is between about 80 μm and about 90μm. In another embodiment, D_(v)(0.5) is between about 70 μm and about80 μm. In some embodiments, the D_(v)(0.5) is about 75 μm.

In other embodiments, the D_(v)50 is between about 20 μm and about 50μm. In another embodiment, D_(v)(0.5) is between about 40 μm and about50 μm. In yet another embodiment, D_(v)(0.5) is between about 20 μm andabout 30 μm. In another embodiment. D_(v)(0.5) is between about 25 μmand about 35 μm. In yet another embodiment, D_(v)(0.5) is between about35 μm and about 45 μm. In another embodiment, D_(v)(0.5) is betweenabout 30 μm and about 40 μm. In yet another embodiment, D_(v)(0.5) isabout 35 μm. In yet another embodiment, D_(v)(0.5) is about 30 μm. Inanother embodiment, D_(v)(0.5) is about 40 μm. In yet anotherembodiment, D_(v)(0.5) is about 45 μm. In another embodiment, D_(v)(0.5)is about 25 μm.

In some embodiments, the D_(v)90—the median particle size by volume anddefined as the maximum particle diameter below which 90% of the samplevolume exists—is between about 40 μm and about 140 μm. In yet anotherembodiment, D_(v)(0.9) is between about 80 μm and about 130 μm. Inanother embodiment, D_(v)(0.9) is between about 90 μm and about 120 μm.In another embodiment, D_(v)(0.9) is between about 90 μm and about 100μm. In another embodiment, D_(v)(0.9) is between about 100 μm and about120 μm. In other embodiments, the D_(v)(0.9) is between about 85 μm andabout 115 μm. In another embodiment, D_(v)(0.9) is between about 100 μmand about 120 μm. In yet another embodiment, D_(v)(0.9) is about 100 μm.In another embodiment, D_(v)(0.9) is about 105 μm. In yet anotherembodiment, D_(v)(0.9) is about 110 μm. In another embodiment,D_(v)(0.9) is about 90 μm. In yet another embodiment, D_(v)(0.9) isabout 95 μm. In yet another embodiment, D_(v)(0.9) is about 85 μm.

In other embodiments, the D_(v)90 is between about 20 μm and about 70μm. In another embodiment, D_(v)(0.9) is between about 20 μm and about60 μm. In yet another embodiment, D_(v)(0.9) is between about 20 μm andabout 40 μm. In another embodiment, D_(v)(0.9) is between about 25 μmand about 35 μm. In yet another embodiment, D_(v)(0.9) is between about40 μm and about 70 μm. In another embodiment, D_(v)(0.9) is betweenabout 40 and about 70 μm. In yet another embodiment, D_(v)(0.9) isbetween about 50 μm and about 70 μm. In another embodiment, D_(v)(0.9)is between about 50 μm and about 60 μm. In yet another embodiment,D_(v)(0.9) is about 55 μm. In another embodiment, D_(v)(0.9) is about 50μm. In yet another embodiment, D_(v)(0.9) is about 30 μm. In anotherembodiment, D_(v)(0.9) is about 35 μm. In yet another embodiment,D_(v)(0.9) is about 40 μm. In another embodiment, D_(v)(0.9) is about 45μm. In yet another embodiment, D_(v)(0.9) is about 55 μm. In anotherembodiment, D_(v)(0.9) is about 60 μm. In yet another embodiment,D_(v)(0.9) is about 25 μm.

In some embodiments, the D_(v)10—the median particle size by volume anddefined as the maximum particle diameter below which 10% of the samplevolume exists—is between about 20 μm and about 100 μm. In yet anotherembodiment, D_(v)(0.1) is between about 20 μm and about 70 μm. Inanother embodiment, D_(v)(0.1) is between about 30 μm and about 60 μm.In yet another embodiment, D_(v)(0.1) is between about 20 μm and about40 μm. In another embodiment, D_(v)(0.1) is between about 20 μm andabout 40 μm. In yet another embodiment, D_(v)(0.1) is between about 40μm and about 60 μm. In another embodiment. D_(v)(0.1) is between about25 μm and about 35 μm. In yet another embodiment, D_(v)(0.1) is betweenabout 45 μm and about 55 μm.

In other embodiments, the D_(v)10 is between about 1 μm and about 60 μm.In another embodiment, D_(v)(0.1) is between about 5 μm and about 30 μm.In yet another embodiment, D_(v)(0.1) is between about 6 μm and about 23μm. In another embodiment, D_(v)(0.1) is between about 15 μm and about25 μm. In another embodiment, D_(v)(0.1) is between about 1 m and about15 μm. In another embodiment, D_(v)(0.1) is between about 1 μm and about10 μm. In another embodiment, D_(v)(0.1) is between about 10 μm andabout 20 μm. In another embodiment, D_(v)(0.1) is about 15 μm. Inanother embodiment, D_(v)(0.1) is about 20 μm.

In these embodiments, D_(v)(0.1) is between about 10 and 80 μm, morepreferably between about 30 and 60 μm, and D_(v)(0.9) is between about80 and 150 μm, more preferably between about 90 and 120 μm. In anotherembodiment, Dv(0.5) is between about 60 and 90 μm. In anotherembodiment, Dv(0.5) is between about 70 and 80 μm.

In some embodiments, the D_(v)(0.5) is between 60 μm and about 90 μm andD_(v)(0.9) is between 80 μm and about 130 μm. In another embodiment, theD_(v)(0.5) is between 70 μm and about 80 μm and D_(v)(0.9) is between 80μm and about 130 μm. In yet another embodiment, the D_(v)(0.5) isbetween 70 μm and about 80 μm and D_(v)(0.9) is between 90 μm and about120 μm.

In another embodiment, the D_(v)(0.5) is between 60 μm and about 90 μm,D_(v)(0.9) is between 80 μm and about 130 μm, D_(v)(0.1) is between 20μm and about 70 μm. In yet another embodiment, the D_(v)(0.5) is between70 μm and about 80 μm, D_(v)(0.9) is between 80 μm and about 130 μm,D_(v)(0.1) is between 20 μm and about 70 μm. In another embodiment, theD_(v)(0.5) is between 60 m and about 90 μm, D_(v)(0.9) is between 90 μmand about 120 μm, D_(v)(0.1) is between 20 μm and about 70 μm. In yetanother embodiment, the D_(v)(0.5) is between 70 μm and about 80 μm,D_(v)(0.9) is between 90 μm and about 120 μm, D_(v)(0.1) is between 20μm and about 70 μm.

In another embodiment, the D_(v)(0.5) is between 60 μm and about 90 μm,D_(v)(0.9) is between 80 μm and about 130 μm, D_(v)(0.1) is between 30μm and about 60 μm. In yet another embodiment, the D_(v)(0.5) is between70 μm and about 80 μm, D_(v)(0.9) is between 80 μm and about 130 μm,D_(v)(0.1) is between 30 μm and about 60 μm. In another embodiment, theD_(v)(0.5) is between 60 μm and about 90 μm, D_(v)(0.9) is between 90 μmand about 120 μm. D_(v)(0.1) is between 30 μm and about 60 μm. In yetanother embodiment, the D_(v)(0.5) is between 70 μm and about 80 μm,D_(v)(0.9) is between 90 μm and about 120 μm, D_(v)(0.1) is between 30μm and about 60 μm.

In another embodiment, the D_(v)(0.5) is between 20 μm and about 50 μm,D_(v)(0.9) is between 40 μm and about 70 μm, D_(v)(0.1) is between 5 μmand about 30 μm. In yet another embodiment, the D_(v)(0.5) is between 30μm and about 40 μm, D_(v)(0.9) is between 40 μm and about 70 μm,D_(v)(0.1) is between 5 μm and about 30 μm. In another embodiment, theD_(v)(0.5) is between 20 μm and about 50 μm, D_(v)(0.9) is between 50 μmand about 60 μm, D_(v)(0.1) is between 5 μm and about 30 μm. In yetanother embodiment, the D_(v)(0.5) is between 30 μm and about 40 μm,D_(v)(0.9) is between 50 μm and about 60 μm, D_(v)(0.1) is between 5 μmand about 30 μm.

In another embodiment, the D_(v)(0.5) is between 20 μm and about 50 μm,D_(v)(0.9) is between 40 μm and about 70 μm, D_(v)(0.1) is between 6 μmand about 23 μm. In yet another embodiment, the D_(v)(0.5) is between 30μm and about 40 μm, D_(v)(0.9) is between 40 μm and about 70 μm,D_(v)(0.1) is between 6 μm and about 23 μm. In another embodiment, theD_(v)(0.5) is between 20 μm and about 50 μm, D_(v)(0.9) is between 50 μmand about 60 μm, D_(v)(0.1) is between 6 μm and about 23 μm. In yetanother embodiment, the D_(v)(0.5) is between 30 μm and about 40 μm,D_(v)(0.9) is between 50 μm and about 60 μm, D_(v)(0.1) is between 6 μmand about 23 μm.

In another embodiment, the D_(v)(0.5) is between 70 μm and about 80 μm,D_(v)(0.9) is between 110 μm and about 120 μm, D_(v)(0.1) is between 50μm and about 60 μm. In yet another embodiment, the D_(v)(0.5) is between50 μm and about 60 μm, D_(v)(0.9) is between 85 μm and about 95 μm,D_(v)(0.1) is between 25 μm and about 35 μm. In another embodiment, theD_(v)(0.5) is between 70 μm and about 80 μm, D_(v)(0.9) is between 100μm and about 110 μm, D_(v)(0.1) is between 50 μm and about 60 μm.

In another embodiment, the D_(v)(0.5) is between 25 μm and about 35 μm,D_(v)(0.9) is between 45 μm and about 55 μm, D_(v)(0.1) is between 10 μmand about 20 μm. In yet another embodiment, the D_(v)(0.5) is between 10μm and about 20 μm, D_(v)(0.9) is between 25 μm and about 35 μm,D_(v)(0.1) is between 1 μm and about 10 μm. In another embodiment, theD_(v)(0.5) is <35 μm, D_(v)(0.9) is <55 μm, D_(v)(0.1) is >5 μm.

In yet another embodiment, D_(v)(0.5) is between about 60 μm and about90 μm. In another embodiment, D_(v)(0.5) is between about 60 μm andabout 70 μm. In another embodiment, D_(v)(0.5) is between about 80 μmand about 90 μm. In another embodiment, D_(v)(0.5) is between about 70μm and about 80 μm. In some embodiments, the D_(v)(0.5) is about 75 μm.

In some embodiments, the ratios of Dv(0.9):Dv(0.5) and Dv(0.5):Dv(0.1)are each independently <2. In another embodiment, the ratio ofDv(0.9):Dv(0.5) is about two or less and the ratio of Dv(0.5):Dv(0.1) isabout five or less. In yet another embodiment, the ratio ofDv(0.9):Dv(0.5) is <1.8. In another embodiment, the ratio ofDv(0.9):Dv(0.5) is about 2.0. In yet another embodiment, the ratio ofDv(0.9):Dv(0.5) is about 1.8. In another embodiment, the ratio ofDv(0.9):Dv(0.5) is about 1.6.

In another embodiment, the ratio of Dv(0.5):Dv(0.1) is <2.0. In yetanother embodiment, Dv(0.5):Dv(0.1) is <1.9. In another embodiment, theratio of Dv(0.5):Dv(0.1) is about 2.0. In yet another embodiment, theratio of Dv(0.5):Dv(0.1) is about 1.8. In another embodiment, the ratioof Dv(0.9):Dv(0.5) is about 1.6.

In another embodiment, the ratio of Dv(0.9):Dv(0.5) is <5.0 and theratio of Dv(0.5):Dv(0.1) is <5.0. In yet another embodiment, the ratioof Dv(0.9):Dv(0.5) is <2.0 and the ratio of Dv(0.5):Dv(0.1) is <2.0. Inanother embodiment, the ratio of Dv(0.9):Dv(0.5) is <1.8 and the ratioof Dv(0.5):Dv(0.1) is <1.8. In another embodiment, the ratio ofDv(0.9):Dv(0.5) is <1.6 and the ratio of Dv(0.5):Dv(0.1) is <2.0.

In some embodiments, the D_(v)50 is about 75 μm. In some embodiments,D_(v)(0.5) is between about 30 and 100 μm. More preferably, D_(v)(0.5)is between about 60 and 90 μm. In these embodiments, D_(v)(0.1) isbetween about 10 and 80 μm, more preferably between about 30 and 60 μm,and D_(v)(0.9) is between about 80 and 150 μm, more preferably betweenabout 90 and 120 μm. In another embodiment, Dv(0.5) is between about 60and 90 μm. In another embodiment, Dv(0.5) is between about 70 and 80 μm.In one embodiment, the ratios of Dv(0.9):Dv(0.5) and Dv(0.5):Dv(0.1) areeach independently less than about two. In one embodiment, the ratio ofDv(0.9):Dv(0.5) is about two or less and the ratio of Dv(0.5):Dv(0.1) isabout five or less.

In other embodiments, D_(v)(0.5) is between about 1 and 25 μm, morepreferably between about 5 and 20 μm. In these embodiments, D_(v)(0.1)is between about 1 and 10 μm, more preferably between about 2 and 6 μm,and D_(v)(0.9) is between about 5 and 50 μm, more preferably betweenabout 20 and 35 μm. In another embodiment, Dv(0.5) is between about 5and 20 μm. In another embodiment, Dv(0.5) is between about 10 and 20 μm.In another embodiment, Dv(0.5) is about 15 μm. In one embodiment, theratios of Dv(0.9):Dv(0.5) and Dv(0.5):Dv(0.1) are each independentlyless than about two. In one embodiment, the ratio of Dv(0.9):Dv(0.5) isabout two or less and the ratio of Dv(0.5):Dv(0.1) is about five orless.

In some embodiments, the particle size distribution is relativelynarrow. For example, 90% of the particles are within the range of 10 μmto 25 μm. In some embodiments, particles are essentially monodispersewith controlled sized from about 5-10 μm.

It has been theorized that small particles, less than 3 μm in diameter,could potentially be absorbed into a patient's bloodstream resulting inundesirable effects such as the accumulation of particles in the urinarytract of the patient, and particularly in the patient's kidneys.Following ingestion, translocation of particles into and across thegastrointestinal mucosa can occur via four different pathways: 1)endocytosis through epithelial cells; 2) transcytosis at the M-cellslocated in the Peyer's Patches (small intestinal lymphoid aggregates),persorption (passage through “gaps” at the villous tip) and 4) putativeparacellular uptake (Powell, J. J. et al Journal of Autoimmunity 2010,34, J226-J233). The most documented and common route of uptake for microparticles is via the M-cell rich layer of Peyer's Patches, especiallyfor small microparticles on the order of 0.1 to 0.5 μm in size (Powell,Journal of Autoimmunity 2010). Thus, excessively small particles, oftencalled the “fines,” should be controlled during the polymermanufacturing process. The presence of such fine particulate mattercould present a safety challenge, and at minimum would impact thenon-absorbed nature of the polymeric drug and associated safetyadvantages.

In another aspect of the invention, the swelling ratios of the polymerparticles have been optimized. In some embodiments, polymers have aswelling ratio of less than about 10 grams of water per gram of polymerand more than about 2 grams of water per gram of polymer. In anotherembodiment, the polymer particles have a swelling ratio of less thanabout 7 grams of water per gram of polymer, but greater than about 2grams of water per gram of polymer. In yet another embodiment, theswelling ratio is less than about 4.5 grams of water per gram ofpolymer, and more than about 3 grams of water per gram of polymer.

In some embodiments, the polymers have a swelling ratio in water ofbetween about 3 grams of water per gram of polymer to about 8 grams ofwater per gram of polymer. In another embodiment, the polymers have aswelling ratio in water of between about 3 grams of water per gram ofpolymer to about 4.5 grams of water per gram of polymer. In yet anotherembodiment, the polymers have a swelling ratio in water of about 4.3grams of water per gram of polymer. In another embodiment, the polymershave a swelling ratio in water of between about 3.5 to about 6.5 gramsof water per gram of polymer. In another embodiment, the polymers have aswelling ratio in water of between about 4.0 to about 6.0 grams of waterper gram of polymer. In another embodiment, the polymers have a swellingratio in water of between about 4.0 to about 5.8 grams of water per gramof polymer.

In some embodiments, the potassium binding polymer is characterized by aswelling ratio in water of between about 3 grams of water per gram ofpolymer to about 8 grams of water per gram of polymer. In anotherembodiment, the potassium binding polymer is characterized by a swellingratio in water of between about 3 grams of water per gram of polymer toabout 4.5 grams of water per gram of polymer. In yet another embodiment,the potassium binding polymer is characterized by a swelling ratio inwater of about 3.3 grams of water per gram of polymer. In anotherembodiment, the potassium binding polymer is characterized by a swellingratio in water of about 4.3 grams of water per gram of polymer.

The present invention provides a method of removing potassium and/ortreating hyperkalemia in an animal subject in need thereof, comprisingadministering an effective amount once, twice or three times per day tothe subject of a crosslinked cation exchange polymer in the form ofsubstantially spherical particles having a well-defined particle sizedistribution and a preferred swelling ratio in water. The particleshape, size distribution and swelling ratio of the polymer is chosen tonot only increase the amount of potassium that can be diverted into thefeces in an animal subject consuming said polymer, but these physicalproperties also improve the palatability (mouth feel, taste, etc.) ofthe polymer when it is ingested by a subject in need thereof. Preferredphysical properties include a generally spherical shape of theparticles, a well-defined particle size distribution with the smallestparticles typically no smaller than 1-2 μm and the largest particlestypically no larger than 100-120 μm, and a swelling ratio between about2 grams of water per gram of polymer to 6 grams of water per gram ofpolymer when measured in water with the polymer in the calcium saltform.

Generally, the potassium binding polymers described herein are notabsorbed from the gastrointestinal tract. The term “non-absorbed” andits grammatical equivalents (such as “non-systemic,” “non-bioavailable,”etc.) is not intended to mean that the polymer cannot be detectedoutside of the gastrointestinal tract. It is anticipated that certainamounts of the polymer may be absorbed. For example, about 90% or moreof the polymer is not absorbed, more particularly, about 95% of thepolymer is not absorbed, and more particularly still about 98% or moreof the polymer is not absorbed.

In some embodiments, the potassium-binding polymers described herein arecrosslinked cation exchange polymers (or “resins”) derived from at leastone crosslinker and at least one monomer. The monomer (or crosslinker)can contain an acid group in several forms, including protonated orionized forms, or in a chemically protected form that can be liberated(“deprotected”) later in the synthesis of the polymer. Alternatively,the acid group can be chemically installed after first polymerizing thecrosslinker and monomer groups. Acid groups can include sulfonic,sulfuric, carboxylic, phosphonic, phosphoric or sulfamic groups, orcombinations thereof. In general, the acidity of the group should besuch that, at physiological pH in the gastrointestinal tract of thesubject in need, the conjugate base is available to interact favorablywith potassium ions.

The polymer of the present invention can be characterized by acrosslinking of between about 0.5% to about 6%. In some embodiments, thepolymer is characterized by a crosslinking of less than 6%. In anotherembodiment, the polymer is characterized by a crosslinking of less than5%. In yet another embodiment, the polymer is characterized by acrosslinking of less than 3%. In another embodiment, the polymer ischaracterized by a crosslinking of about 1.8%, wherein the term “about”means±20%. In yet another embodiment, the polymer is characterized by acrosslinking of about 1.8%, wherein the term “about” means±10%. Inanother embodiment, the polymer is characterized by a crosslinking ofabout 1.8%, wherein the term “about” means±5%. In other embodiments, thepolymer is characterized by a crosslinking of 1.0%, 1.1%, 1.2%, 1.3%,1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%,2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%,3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%,or 5.0%.

The ratio of monomer(s) to crosslinker(s) can be chosen to affect thephysical properties of the polymer. Additional factors include the timeof addition of the crosslinker, the time and temperature of thepolymerization reaction, the nature of the polymerization initiator, theuse of different additives to help modulate agglomeration of the growingpolymer or otherwise stabilize reactants prior to, or during, thepolymerization process. The ratio of the monomer(s) and crosslinker(s),or the “repeat units,” can be chosen by those of skill in the art basedon the desired physical properties of the polymer particles. Forexample, the swelling ratio can be used to determine the amount ofcrosslinking based on general principles that indicate that ascrosslinking increases, the selling ratio in water generally decreases.In one specific embodiment, the amount of crosslinker in thepolymerization reaction mixture is in the range of 1 wt. % to 10 wt. %,more specifically in the range of 1 wt. % to 8 wt. %, and even morespecifically in the range of 1.8 wt. % to 2.5 wt. %. To one skilled inthe art, these weight ratios can be converted to mole ratios—based onthe molecular weights of said monomers—and these mole-based calculationscan be used to assign numerical values to “m” and “n” in (Formula I). Itis also noted that to one skilled in the art that in practice,individual monomers can react at different rates and hence theirincorporation into the polymer is not necessarily quantitative. Withthis in mind, the amount of crosslinker in the polymerization reactionmixture is in the range of 1 mole % to 8 mole %, more specifically inthe range of 1 mole % to 7 mole %, and even more specifically in therange of 1.5 mole % to 2 mole %.

In another aspect of the invention, the polymers of the invention have amouth feel score greater than 3. In some embodiments, the polymers havea mouth feel score greater than 3.5. In another embodiment, the polymershave a mouth feel score greater than 4.0. In yet another embodiment, thepolymers have a mouth feel score greater than 5.0. In anotherembodiment, the polymers of the invention have a mouth feel score ofbetween about 3.0 to about 6.0. In yet another embodiment, the polymersof the invention have a mouth feel score of between about 4.0 to about6.0. In another embodiment, the polymers of the invention have a mouthfeel score of between about 5.0 to about 6.0.

The polymers of the invention can also have a grittiness score that isgreater than 3. In some embodiments, the polymers have a grittinessscore greater than 3. In another embodiment, the polymers have agrittiness score greater than 4. In yet another embodiment, the polymershave a grittiness score greater than 4.5. In another embodiment, thepolymers have a grittiness score greater than 5. In another embodiment,the polymers have a grittiness score greater than 5.5. In yet anotherembodiment, the polymers have a grittiness score of between about 3.0 toabout 6.0. In yet another embodiment, the polymers have a grittinessscore of between about 3.5 to about 6.0. In yet another embodiment, thepolymers have a grittiness score of between about 4.5 to about 6.0

DEFINITIONS

“Amino” refers to the —NH₂ radical.

“Aminocarbonyl” refers to the —C(═O)NH₂ radical.

“Carboxy” refers to the —CO₂H radical. “Carboxylate” refers to a salt orester thereof.

“Cyano” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” or “carbonyl” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Guanidinyl” (or “guanidine”) refers to the —NHC(═NH)NH₂ radical.

“Amidinyl” (or “amidine”) refers to the —C(═NH)NH₂ radical.

“Phosphate” refers to the —OP(═O)(OH)₂ radical.

“Phosphonate” refers to the —P(═O)(OH)₂ radical.

“Phosphinate” refers to the —PH(═O)OH radical, wherein each R^(a) isindependently an alkyl group as defined herein.

“Sulfate” refers to the —OS(═O)₂OH radical.

“Sulfonate” or “hydroxysulfonyl” refers to the —S(═O)₂OH radical.

“Sulfinate” refers to the —S(═O)OH radical.

“Sulfonyl” refers to a moiety comprising a —SO₂— group. For example,“alkysulfonyl” or “alkylsulfone” refers to the —SO₂—R^(a) group, whereinR^(a) is an alkyl group as defined herein.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds),having from one to twelve carbon atoms (C₁₋₁₂ alkyl), preferably one toeight carbon atoms (C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆alkyl), and which is attached to the rest of the molecule by a singlebond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkyl group may be optionally substituted.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds), andhaving from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, ethenylene, propenylene, n-butenylene,propynylene, n-butynylene, and the like. The alkylene chain is attachedto the rest of the molecule through a single or double bond and to theradical group through a single or double bond. The points of attachmentof the alkylene chain to the rest of the molecule and to the radicalgroup can be through one carbon or any two carbons within the chain.Unless stated otherwise specifically in the specification, an alkylenechain may be optionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, an alkoxygroup may be optionally substituted.

“Alkylamino” refers to a radical of the formula —NHR_(a) or —NR_(a)R_(a)where each R_(a) is, independently, an alkyl radical as defined abovecontaining one to twelve carbon atoms. Unless stated otherwisespecifically in the specification, an alkylamino group may be optionallysubstituted.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, a thioalkylgroup may be optionally substituted.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals that are optionally substituted.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example benzyl, diphenylmethyl and thelike. Unless stated otherwise specifically in the specification, anaralkyl group may be optionally substituted.

“Cycloalkyl” or “carbocyclic ring” refers to a stable non-aromaticmonocyclic or polycyclic hydrocarbon radical consisting solely of carbonand hydrogen atoms, which may include fused or bridged ring systems,having from three to fifteen carbon atoms, preferably having from threeto ten carbon atoms, and which is saturated or unsaturated and attachedto the rest of the molecule by a single bond. Unless otherwise statedspecifically in the specification, a cycloalkyl group may be optionallysubstituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(d) whereR_(d) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group may be optionally substituted.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above that issubstituted by one or more halo radicals, as defined above. Unlessstated otherwise specifically in the specification, a haloalkyl groupmay be optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a stable 3- to18-membered non-aromatic ring radical which consists of two to twelvecarbon atoms and from one to six heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur. Unless stated otherwisespecifically in the specification, the heterocyclyl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems; and the nitrogen, carbon orsulfur atoms in the heterocyclyl radical may be optionally oxidized; thenitrogen atom may be optionally quaternized; and the heterocyclylradical may be partially or fully saturated. Unless stated otherwisespecifically in the specification, a heterocyclyl group may beoptionally substituted.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. Unless stated otherwisespecifically in the specification, a N-heterocyclyl group may beoptionally substituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(e) whereR_(b) is an alkylene chain as defined above and R_(e) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. Unless stated otherwisespecifically in the specification, a heterocyclylalkyl group may beoptionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems, and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Unless stated otherwise specifically in the specification,a heteroaryl group may be optionally substituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. Unless stated otherwise specifically inthe specification, an N-heteroaryl group may be optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(f) whereR_(b) is an alkylene chain as defined above and R_(f) is a heteroarylradical as defined above. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group may be optionally substituted.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl)wherein at least one hydrogen atom is replaced by a bond to anon-hydrogen atoms such as, but not limited to: a halogen atom such asF, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups,carboxyl groups, phosphate groups, sulfate groups, alkoxy groups, andester groups; a sulfur atom in groups such as thiol groups, thioalkylgroups, sulfinate groups, sulfone groups, sulfonyl groups, and sulfoxidegroups; a phosphorus atom in groups such as phosphinate groups andphosphonate groups; a nitrogen atom in groups such as guanidine groups,amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines,diarylamines, N-oxides, imides, and enamines; a silicon atom in groupssuch as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilylgroups, and triarylsilyl groups; and other heteroatoms in various othergroups. “Substituted” also means any of the above groups in which one ormore hydrogen atoms are replaced by a higher-order bond (e.g., a double-or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl,carboxyl, and ester groups; and nitrogen in groups such as imines,oximes, hydrazones, and nitriles. For example, “substituted” includesany of the above groups in which one or more hydrogen atoms are replacedwith —NR_(g)R_(h), —NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h),—NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g),—SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and—SO₂NR_(g)R_(h). “Substituted” also means any of the above groups inwhich one or more hydrogen atoms are replaced with —C(═O)R_(g),—C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), —CH₂SO₂NR_(g)R_(h),—(CH₂CH₂O)₁₋₁₀R_(g), —(CH₂CH₂O)₂₋₁₀R_(g), —(OCH₂CH₂)₁₋₁₀R_(g) and—(OCH₂CH₂)₂₋₁₀R_(g). In the foregoing, R_(g) and R_(h) are the same ordifferent and independently hydrogen, alkyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any ofthe above groups in which one or more hydrogen atoms are replaced by abond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo,alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkylgroup. The above non-hydrogen groups are generally referred to herein as“substituents” or “non-hydrogen substituents”. In addition, each of theforegoing substituents may also be optionally substituted with one ormore of the above substituents.

By “crosslink” and “crosslinking” is meant a bond or chain of atomsattached between and linking two different polymer chains.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

Unless specifically stated, as used herein, the term “about” refers to arange of values ±10% of a specified value. For example, the phrase“about 200” includes ±10% of 200, or from 180 to 220. When statedotherwise the term about will refer to a range of values that include±20%, ±10%, or ±5%, etc.

The term “activate” refers to the application of physical, chemical, orbiochemical conditions, substances or processes that a receptor (e.g.,pore receptor) to structurally change in a way that allows passage ofions, molecules, or other substances.

The term “active state” refers to the state or condition of a receptorin its non-resting condition.

“Efflux” refers to the movement or flux of ions, molecules, or othersubstances from an intracellular space to an extracellular space.

“Enteral” or “enteric” administration refers to administration via thegastrointestinal tract, including oral, sublingual, sublabial, buccal,and rectal administration, and including administration via a gastric orduodenal feeding tube.

The term “inactive state” refers to the state of a receptor in itsoriginal endogenous state, that is, its resting state.

The term “modulating” includes “increasing” or “enhancing,” as well as“decreasing” or “reducing,” typically in a statistically significant ora physiologically significant amount as compared to a control. An“increased” or “enhanced” amount is typically a “statisticallysignificant” amount, and may include an increase that is about 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.3, 4.4, 4.6, 4.8, 5,6, 7, 8, 9, 10, 15, 20, 30, 40, 50 or more times (e.g., 100, 200, 500,1000 times) (including all integers and decimal points and ranges inbetween and above 1, e.g., 5.5, 5.6, 5.7, 5.8, etc.) the amount producedby a control (e.g., the absence or lesser amount of a compound, adifferent compound or treatment), or the amount of an earlier time-point(e.g., prior to treatment with a compound). A “decreased” or “reduced”amount is typically a “statistically significant” amount, and mayinclude a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% decrease (including allintegers and decimal points and ranges in between) in the amount oractivity produced by a control (e.g., the absence or lesser amount of acompound, a different compound or treatment), or the amount of anearlier time-point (e.g., prior to treatment with a compound).

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

The term “mouthfeel” of a substance according to the present inventionis the tactile sensations perceived at the lining of the mouth,including the tongue, gums and teeth.

“Optional” or “optionally” means that the subsequently described eventor circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

By “statistically significant,” it is meant that the result was unlikelyto have occurred by chance. Statistical significance can be determinedby any method known in the art. Commonly used measures of significanceinclude the p-value, which is the frequency or probability with whichthe observed event would occur, if the null hypothesis were true. If theobtained p-value is smaller than the significance level, then the nullhypothesis is rejected. In simple cases, the significance level isdefined at a p-value of 0.05 or less.

“Substantially” or “essentially” includes nearly totally or completely,for instance, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater of somegiven quantity.

The term “secondary” refers to a condition or state that can occur withanother disease state, condition, or treatment, can follow on fromanother disease state, condition, or treatment, or can result fromanother disease state, condition or treatment. The term also refers tosituations where a disease state, condition, or treatment can play onlya minor role in creating symptoms or a response in a patient's finaldiseased state, symptoms or condition.

“Subjects” or “patients” (the terms are used interchangeably herein) inneed of treatment with a compound of the present disclosure include, forinstance, subjects “in need of potassium lowering.” Included are mammalswith diseases and/or conditions described herein, particularly diseasesand/or conditions that can be treated with the compounds of theinvention, with or without other active agents, to achieve a beneficialtherapeutic and/or prophylactic result. A beneficial outcome includes adecrease in the severity of symptoms or delay in the onset of symptoms,modulation of one or more indications described herein (e.g., reducedpotassium ion levels in serum or blood of patients with or at risk forhyperkalemia, increased fecal output of potassium ions in patients withor at risk for hyperkalemia), increased longevity, and/or more rapid ormore complete resolution of the disease or condition.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

A “therapeutically effective amount” or “effective amount” includes anamount of a compound of the invention which, when administered to amammal, preferably a human, is sufficient to increase fecal output ofpotassium ions, reduce serum levels of potassium ions, treathyperkalemia in the mammal, preferably a human, and/or treat any one ormore other conditions described herein. The amount of a compound of theinvention which constitutes a “therapeutically effective amount” willvary depending on the compound, the condition and its severity, themanner of administration, and the age of the mammal to be treated, butcan be determined routinely by one of ordinary skill in the art havingregard to his own knowledge and to this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or

(iv) relieving the symptoms resulting from the disease or condition,i.e., relieving pain without addressing the underlying disease orcondition. As used herein, the terms “disease” and “condition” may beused interchangeably or may be different in that the particular maladyor condition may not have a known causative agent (so that etiology hasnot yet been worked out) and it is therefore not yet recognized as adisease but only as an undesirable condition or syndrome, wherein a moreor less specific set of symptoms have been identified by clinicians.

Methods of Making the Potassium Binding Crosslinked Polymers

Copolymerization of an Organic Monomer “R₁—X” Displaying a Single Olefinwith a “Crosslinker” Organic Monomer “R₂—Y” that Displays Two Olefins.

Scheme 1 illustrates the copolymerization of an organic monomerdisplaying a single olefin (R₁—X—CH═CH—R₃) with a second organic monomerdisplaying two olefin groups (R₂—Y—(CH═CH—R₃)₂; a crosslinker). R₁ andR₂ can be —H, acidic functional groups such as sulfonic, sulfuric,carboxylic, phosphonic, phosphoric or sulfamic groups, or combinationsthereof, or substituted or unsubstituted alkyl or aryl radicals. R₃ canbe —H, halogen, acidic functional groups such as sulfonic, sulfuric,carboxylic, phosphonic, phosphoric or sulfamic groups, or combinationsthereof, or substituted or unsubstituted alkyl or aryl radicals. X and Ycan be the same or different, and can be substituted or unsubstitutedalkyl or aryl radicals. More preferably, R₁—X represents an aromaticgroup, and R₂—Y represents an aromatic group. Most preferably, R₁—X isphenyl and R₂—Y is phenyl and R₃ is —H—hence R₁—X—CH═CH—R₃ is styreneand R₂—Y—(CH═CH—R₃)₂ is divinylbenzene. Divinylbenzene can be ortho-,meta- or para-divinylbenzene, and is most commonly a mixture of two orthree of these isomers. When R₁—X is phenyl, R₂—Y is phenyl and R₃ is—H, the resulting polymer is further modified to display acidicfunctionality capable of binding to potassium ions. In a preferredembodiment, the polymer is sulfonated by treatment with concentratedsulfuric acid, optionally using a catalyst such as silver sulfate. Theresulting sulfonylated material can be retained in its acid form, oralternatively treated with base and converted to a salt form. This saltform can include metal salts such as sodium, calcium, magnesium or ironsalts. These can also be organic salts, including salts of amines oramino acids and the like. In a preferred embodiment, the calcium salt isformed. In this preferred embodiment, (I) in Scheme 1 consists ofX=Y=phenyl (Ph), R₁=R₂=—SO₃ ⁻[0.5 Ca²⁺], and R₃ is —H. In this preferredembodiment, the ratio of m to n (m:n) is about: 11:1 to about 120:1,more preferably about 14:1, more preferably still about 40:1, and mostpreferably about 50:1, about 60:1, and about 70:1.

In one embodiment, the polymer is prepared from structural units ofFormula 1 (e.g. styrene) and Formula 2 (e.g., divinylbenzene), whichafford a polystyrene divinylbenzene copolymer intermediate. The weightratio of the structural units of Formula 1 to Formula 2 is such that thepolymer consists of about 90% Formula 1 and 10% of Formula 2. It shouldbe noted, that in most cases, Formula 2 can be a mixture. In the case ofdivinylbenzene, the ortho, meta, and para positional isomers can bepresent Most preferable compositions include about 97.5% Formula 1 and2.5% Formula 2, 98% Formula 1 and 2% Formula 2, and 98.2% Formula 1 and1.8% Formula 2, by weight. Scheme 2 illustrates a copolymerization ofthis description, where “m” and “n” in the product reflect the varyingamounts of styrene (m) and divinylbenzene (n).

In one embodiment, the polymerization initiator used in the suspensionpolymerization plays a role in the quality of the polymer particles,including yield, shape and other physical attributes. Without beingbound to a particular theory, the use of water-insoluble free radicalinitiators, such as benzoyl peroxide, initiates polymerization primarilywithin the phase containing the monomers. Such a reaction strategyprovides polymer particles rather than a bulk polymer gel. Othersuitable free radical initiators include other peroxides such as lauroylperoxide (LPO), tert-butyl hydro peroxide, and the like. Azo typeinitiators commonly include azobisisobutyronitrile (AIBN), but also usedare dimethyl-2,2′-azobis(2-methyl-proprionate), 2,2″-azobis(2,4-dimethylvaleronitrile) and the like. These agents initiate thepolymerization process.

Additional polymerization components that are not intended to beincorporated into the polymer include additives such as surfactants,solvents, salts, buffers, aqueous phase polymerization inhibitors and/orother components known to those of skill in the art. When thepolymerization is carried out in a suspension mode, the additionalcomponents may be contained in an aqueous phase while the monomers andinitiator may be contained in an organic phase. A surfactant may beselected from the group consisting of anionic, cationic, nonionic,amphoteric or zwitterionic, or a combination thereof. Anionicsurfactants are typically based on sulfate, sulfonate or carboxylateanions and include sodium dodecyl sulfate (SDS), ammonium laurylsulfate, other alkyl sulfate salts, sodium laureth sulfate (or sodiumlauryl ether sulfate (SLES)), N-lauroylsarcosine sodium salt,lauryldimethylamine-oxide (LDAO), ethyltrimethylammoniumbromide (CTAB),bis(2-ethylhexyl)sulfosuccinate sodium salt, alkyl benzene sulfonate,soaps, fatty acid salts, or a combination thereof. Cationic surfactants,for example, contain quaternary ammonium cations. These surfactants arecetyl trimethylammonium bromide (CTAB or hexadecyl trimethyl ammoniumbromide), cetylpyridinium chloride (CPC), polyethoxylated tallow amine(POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT), or acombination thereof. Zwitterionic or amphoteric surfactants includedodecyl betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine,coco ampho glycinate, or a combination thereof. Nonionic surfactantsinclude alkyl poly(ethylene oxide), copolymers of poly(ethylene oxide)and poly(propylene oxide) (commercially called Poloxamers orPoloxamines), alkyl polyglucosides (including octyl glucoside, decylmaltoside), fatty alcohols, cetyl alcohol, oleyl alcohol, cocamide MEA,cocamide DEA, or a combination thereof. Other pharmaceuticallyacceptable surfactants are well known in the art and are described inMcCutcheon's Emulsifiers and Detergents, N. American Edition (2007).

Polymerization reaction stabilizers may be selected from the groupconsisting of organic polymers and inorganic particulate stabilizers.Examples include polyvinyl alcohol-co-vinyl acetate and its range ofhydrolyzed products, polyvinylacetate, polyvinylpyrrolidinone, salts ofpolyacrylic acid, cellulose ethers, natural gums, or a combinationthereof. Buffers may be selected from the group consisting of4-2-hydroxyethyl-1-piperazineethanesulfonic acid,2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid,3-(N-morpholino)propanesulfonic acid,piperazine-N,N′-bis(2-ethanesulfonic acid), sodium phosphate dibasicheptahydrate, sodium phosphate monobasic monohydrate or a combinationthereof.

Generally, the mixture of monomers and additives are subjected topolymerization conditions. These can include suspension polymerizationconditions as well as bulk, solution or emulsion polymerizationprocesses. The polymerization conditions typically includepolymerization reaction temperatures, pressures, mixing and reactorgeometry, sequence and rate of addition of polymerization mixtures andthe like. Polymerization temperatures are typically in the range ofabout 50° C. to 100° C. Polymerizations are typically performed atatmospheric pressures, but can be run at higher pressures (for example130 PSI of nitrogen). Mixing depends upon the scale of thepolymerization and the equipment used, but can include agitation withthe impeller of a reactor to the use of immersion or in-linehomogenizers capable of creating smaller droplets under certainconditions.

In one embodiment, polymerization can be achieved using a suspensionpolymerization approach. Suspension polymerization is a heterogeneousradical polymerization process. In this approach, mechanical agitationis used to mix a monomer or mixture of monomers in an immiscible liquidphase, such as water. While the monomers polymerize, they retain theirnearly spherical suspension shape, forming spheres of polymer.Polymerization suspension stabilizers, such as polyvinyl alcohol, can beused to prevent coalescence of particles during the polymerizationprocess. Factors such as the ratio of monomers to cross linker,agitation speed, ionic strength of the liquid phase, the nature of thesuspension stabilizer, etc., contribute to the yield, shape, size andother physical properties of the polymer.

In one embodiment, highly uniform sized particles can be produced via amulti-step approach inspired by Ugelstad (Ugelstad_1979). In thisapproach, “seeds” are first prepared by dispersion polymerization ofstyrene in the presence of a steric stabilizer such aspolyvinylpyrrolidone, using an initiator such as AIBN, and using awater/alcohol polymerization medium. The seeds are isolated, and thenswollen with a monomer-initiator solution containing additional styreneas well as divinylbenzene and BPO, and then polymerized to give highlyuniform styrene-divinylbenzene beads. Alternatively, a jetting processusing vibrating nozzles can also be used to create microdisperseddroplets of monomers, and in this fashion permit the synthesis of highlyuniform crosslinked polymer beads (Dow Chemical, U.S. Pat. No.4,444,961.)

In another embodiment, the crosslinked styrene-sulfonate particles ofthe invention can be produced by an inverse suspension process, whereina solution of styrene-sulfonate, a water soluble crosslinker and afree-radical initiator are dispersed in an organic solvent and convertedto crosslinked beads.

The polymers illustrated in Scheme 1 and Scheme 2 are most preferablysulfonylated, and the resulting sulfonic acid converted to apharmaceutically acceptable salt. Scheme 3 illustrates the sulfonationof a preferred embodiment. The resulting sulfonic acid can be furthertreated with calcium acetate to afford the calcium salt. At thephysiological pH within the gastrointestinal tract of a subject in need,the conjugate base of the sulfonic acid is available to interactfavorably with potassium ions. By interacting favorably, this meansbinding to or otherwise sequestering potassium cations for subsequentfecal elimination.

Polymer Sulfonylation

Resins comprising the general structure of polystyrene sulfonate crosslinked with divinylbenzene are available and used clinically, e.g.,Kayexalate®, Argamate®, Kionex® and Resonium®. However, these resins donot possess the optimized cross-linking, particle shape, particle sizedistribution, and swelling properties as do the novel polymers describedherein. For example, the crosslinked cation exchange polymers describedin this invention generally have a higher efficacy for potassium in vivothan resins such as Kayexalate. When healthy rodents are administeredthe polymers of the present invention, approximately 1.4- to 1.5-foldmore potassium is excreted fecally than is achieved when, for example,Resonium is similarly dosed (same dosing and fecal collectionconditions). In some embodiments, approximately 2.0-fold more potassiumis excreted fecally than is achieved when, for example, Na-PSS, USP(e.g. Kavexylate) is similarly dosed (same dosing and fecal collectionconditions). The higher capacity of the polymers of this invention mayenable the administration of a lower dose of the polymer. Typically, thedose of Na-PSS or Ca-PSS used clinically to obtain the desiredtherapeutic and/or prophylactic benefits is about 10 to 60 grams/day andcan be as high as 120 g/day. A typical dose range is 10-20 g, 30-40 gand 45-120 g, which can be divided into one, two or three doses/day(Fordjour, Am. J. Med. Sci. 2014). The polymers of the current inventioncould permit a significant reduction in drug load for the patient.

Methods of Using Potassium Binding Crosslinked Polymers

Patients suffering from CKD and/or CHF can be particularly in need ofpotassium removal because agents used to treat these conditions maycause potassium retention. Many of these subjects are also takingmedications that interfere with potassium excretion, e.g.,potassium-sparing diuretics, RAAS inhibitors, beta blockers, aldosteronesynthase inhibitors, non-steroidal anti-inflammatory drugs, heparin, ortrimethoprim. In certain particular embodiments, the polymers of thepresent invention can be administered on a periodic basis to treatchronic hyperkalemia. Such a treatment would enable patients to continueusing drugs that may cause hyperkalemia. Also, use of the polymercompositions described herein will enable patient populations, who werepreviously unable to use the above-listed medications, to beingtreatable with these beneficial therapeutics.

The cation exchange polymers described herein can be delivered to thepatient using a wide variety of routes or modes of administration. Themost preferred routes are oral, intestinal (e.g., via gastrointestinaltube) or rectal. Rectal routes of administration are known to those ofskill in the art. The most preferred route for administration is oral.

The polymers described herein can be administered as neat, dry powdersor in the form of a pharmaceutical composition wherein the polymer is inadmixture with one or more pharmaceutically acceptable excipients. Thesecan include carriers, diluents, binder, disintegrants and other suchgenerally-recognized-as-safe (GRAS) excipients designed to present theactive ingredient in a form convenient for consumption by the patient.The nature and composition of these excipients are dependent upon thechosen route of administration.

For oral administration, the polymer can be formulated by combining thepolymer particles with pharmaceutically acceptable excipients well knownin the art. These excipients can enable the polymer to be formulated asa suspension (including thixotropic suspensions), tablets, capsules,dragees, gels (including gummies or candies), syrups, slurries, wafers,liquids, and the like, for oral ingestion by a patient. In oneembodiment, the oral composition does not have an enteric coating.Pharmaceutical preparations for oral use can be obtained as a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose or sucrose; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone (PVP); and various flavoring agents known in theart. If desired, disintegrating agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof such as sodium alginate.

In various embodiments, the active ingredient (e.g., the polymer)constitutes over about 10%, more particularly over about 30%, even moreparticularly over about 60%, and most particularly more than about 80%by weight of the oral dosage form, the remainder comprising suitableexcipient(s).

In a certain formulation, the excipients would be chosen such that thepolymers of the herein invention are well dispersed and suspended, suchthat any sensation of particulate matter on the palate is significantlyblunted or eliminated. Such formulations could include, for example,suspension as a gel or paste in an aqueous matrix of agar, or gelatin,or pectin, or carrageenan, or a mixture of such agents. Such aformulation would be of a sufficient density to suspend the polymerparticles in a non-settling matrix. Flavorings, such as sweeteners canbe added, and these sweeteners can include both nutritive (malt extract,high-fructose corn syrup, and the like) and non-nutritive (e.g.,aspartame, nutrasweet, and the like) agents, which can create a pleasanttaste. Lipids such as tripalmitin, castor oil, sterotex, and the like,can be used to suspend particles in a way that avoids a foreignsensation on the palate, and can also lead to favorable flavorproperties. Milk solids, cocoa butter and chocolate products can becombined to create a pudding or custard type mixture that both suspendthe polymers of the invention, and also mask their contact on thepalate. Formulations of the type described herein should be readilyingested presentations for the patient.

EXAMPLES

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures herein described. It is to be understood thatthe examples are provided to illustrate certain embodiments and that nolimitation to the scope of the disclosure is intended thereby. It is tobe further understood that resort may be had to various otherembodiments, modifications, and equivalents thereof which may suggestthemselves to those skilled in the art without departing from the spiritof the present disclosure and/or scope of the appended claims.

Example 1 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with 8%DVB, 200-400 Mesh Size

Crosslinked (8%) Polystyrene sulfonate beads (200-400 mesh size) in theacid form (H+) were obtained from Sigma-Adrich (Catalog #217514). Thebeads (100 g, wet weight) were suspended in aqueous NaOH (1M, 300 mL)and shaken for 20 hours at 27° C., then the mixture was filtered, andthe wet beads washed with water (2×300 mL). The beads were suspended inaqueous CaCl₂ (0.5M, 700 mL) and shaken for 2 days at 37° C. The beadswere then filtered, and suspended in fresh CaCl₂ (0.5M, 700 mL), andshaken for 2 days at 37° C. The beads were then filtered, washedsuccessively with water (3×400 mL), and dried under reduced pressure togive 56.9 g of Example 1 as a fine light brown sand. Approximateparticle size range of 30-120 μm determined by digital visualmicroscopy.

Example 2 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with 4%DVB, 200-400 Mesh Size

Example 2 was prepared from 100 g crosslinked (4%) polystyrene sulfonatebeads (200-400 mesh), H⁺ form, obtained from Sigma-Adrich (Catalog#217484) using the procedures described in Example 1 to give 37.1 g ofExample 2 as a fine light brown powder. Approximate particle size rangeof 30-130 μm determined by digital visual microscopy.

Example 3 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with 2%DVB, 200-400 Mesh Size

Example 3 was prepared from 100 g crosslinked (2%) polystyrene sulfonatebeads (200-400 mesh), H⁺ form, obtained from Sigma-Aldrich (Catalog#217476) using the procedures described in Example 1 to give 21.8 g ofExample 3 as a light brown sand: Particle size: d_(v)(0.1)=90 μm;d_(v)(0.5)=120 μm; d_(v)(0.9)=170 μm.

Example 4 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with 2%DVB, 200-400 Mesh Size

Crosslinked (2%) Polystyrene sulfonate beads (200-400 mesh size) in theacid form (H+) were obtained from Sigma-Aldrich (Catalog #217476). Thebeads (400 g, wet weight) were suspended in aqueous CaCl₂ (200 g CaCl₂,1.8 L water) and shaken for 24 hours at 38° C., then the mixture wasfiltered. The beads were suspended in aqueous Ca(OAc)₂ (166 g, 2 Lwater) and shaken for 2 days at 37° C. The beads were then filtered,washed with water (1 L), and dried under reduced pressure to giveExample 4 as a light brown sand. Approximate particle size range of40-160 μm determined by digital visual microscopy.

Example 5 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with 4%DVB, 200-400 Mesh Size

Example 5 was prepared from 400 g crosslinked (4%) polystyrene sulfonatebeads (200-400 mesh). H⁺ form, obtained from Sigma-Aldrich (Catalog#217484) using the procedures described in Example 4 to give Example 5as a light brown sand. Approximate particle size range of 30-130 μmdetermined by digital visual microscopy.

Example 6 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with 8%DVB, 200-400 Mesh Size

Example 6 was prepared from 400 g crosslinked (8%) polystyrene sulfonatebeads (200-400 mesh), H⁺ form, obtained from Sigma-Aldrich (Catalog#217514) using the procedures described in Example 4 to give Example 6as a light brown sand. Approximate particle size range of 30-120 μmdetermined by digital visual microscopy.

Example 7 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with0.96% Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 0.96% DVB:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added polyvinyl alcohol (10 g),NaCl (10 g), NaNO₂ (0.2 g) and water (1 L). The mixture was stirred andheated to 70° C. for 1 hour to form a slightly turbid solution. In aseparate container, styrene (75 mL), divinylbenzene (0.94 mL, 80%Technical Grade), and benzoyl peroxide (3 g, 98%) were mixed to form ahomogeneous solution of monomers and initiator. The monomer-initiatorsolution was added to the hot aqueous solution and within 1-2 minutes auniform white suspension was achieved with 600 RPM stirring. The mixturewas heated to 85° C. for 18 hours, and then filtered while hot using acoarse fritted funnel. The solid polystyrene beads were suspended inwater (700 mL), and heated at 85° C. for 1 hour. The mixture was thenfiltered while hot using a coarse fritted funnel, and the polystyrenebeads were suspended in methanol (700 mL), and heated at reflux for 1hour. The mixture was then filtered while still hot using a coarsefritted funnel, and dried in a vacuum oven to give 61 g of polystyrenebeads as a white powder. Particle size estimated by visual microscopyd(50)=40 μm.

Example 7

To a 1 L round bottom flask, equipped with overhead stirrer, N₂ inlet,and a thermocouple was added silver sulfate (0.4 g) and sulfuric acid(98%, 300 mL). The mixture was warmed to 80° C. to dissolve, and thenpolystyrene beads (20 g) were added and the mixture stirred to form asuspension. The mixture was warmed to 100° C. for 3 hours, then pouredinto ice cold 50% aqueous H₂SO₄ (3 kg) The mixture was then diluted to afinal volume of 5 L with water and allowed to stand overnight to settle.The dark supernatant was discarded, and the bead layer filtered using acoarse fritted funnel. The beads were washed with water until the pH ofthe filtrate was >4, as measured by pH indicator strips. The wet beadswere then suspended in aqueous Ca(OAc)₂ (20% wt, 0.5 L) and shaken for24 hours at 37° C., then the mixture was filtered, and the beadssuspended in new aqueous Ca(OAc)₂ (20% wt, 0.5 L) and shaken again for24 hours at 37° C. The beads were then washed successively with water(3×150 mL), and dried under reduced pressure at 50° C. to give 27.4 g ofExample 7 Ca-PSS resin as a light brown sand. Swelling ratio in DIwater: 9.1 g/g with relative centrifugal force of 2000×g; ResidualStyrene: Not Detected (<0.1 ppm).

Example 8 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.12% Divinylbenzene (DVB)

Example 8 was prepared from styrene (75 mL), and divinylbenzene (1.1 mL,80% Technical Grade) using the procedure described in Example 7 to giveapproximately 25 g of Example 8 Ca-PSS resin as a light brown sand.Swelling ratio in DI water: 7.9 g/g with relative centrifugal force of2000×g; Residual Styrene: Not Detected (<0.1 ppm)

Example 9 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.6% Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 1.6% DVB:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added polyvinyl alcohol (10 g),NaCl (10 g), NaNO₂ (0.2 g) and water (1 L). The mixture was stirred andheated to 70° C. for 1 hour to form a slightly turbid solution. In aseparate container, styrene (75 mL), divinylbenzene (1.5 mL, 80%Technical Grade), and benzoyl peroxide (3 g, 98%) were mixed to form ahomogeneous solution of monomers and initiator. The monomer-initiatorsolution was added to the hot aqueous solution and within 1-2 minutes auniform white suspension was achieved with 600 RPM stirring. The mixturewas heated to 85° C. for 18 hours, and then filtered while hot using acoarse fritted funnel. The solid polystyrene beads were suspended inwater (1 L), and heated at 85° C. for 1 hour. The mixture was thenfiltered while hot using a coarse fritted funnel, and the polystyrenebeads were suspended in methanol (1 L), and heated at reflux for 1 hour.The mixture was then filtered while still hot using a coarse frittedfunnel, and dried in a vacuum oven to give 61 g of polystyrene beads asa white powder. Particle size: d(0.1)=27 μm; d(0.5)=40 μm; d(0.9)=60 μm.

Example 9

To a 1 L round bottom flask, equipped with overhead stirrer, N₂ inlet,and a thermocouple was added silver sulfate (0.4 g) and sulfuric acid(98%, 300 mL). The mixture was warmed to 80° C. to dissolve, and thenpolystyrene beads (20 g) were added and the mixture stirred to form asuspension. The mixture was warmed to 100° C. for 3 hours, then pouredinto ice cold 50% aqueous H₂SO₄ (3 kg). The mixture was then diluted toa final volume of 5 L with water and allowed to stand overnight tosettle. The dark supernatant was discarded, and the bead layer filteredusing a coarse fritted funnel. The beads were washed with water untilthe pH of the filtrate was >4, as measured by pH indicator strips. Asample of wet beads were then suspended in aqueous Ca(OAc)₂ (20% wt, 1L) and shaken for 24 hours at 37° C., then the mixture was filtered, andthe beads suspended in new aqueous Ca(OAc)₂ (20% wt, 1 L) and shakenagain for 24 hours at 37° C. The beads were then washed successivelywith water (3×150 mL), 50% EtOH-water (2×150 mL), 75% EtOH-water (2×150mL), and 100% EtOH (2×150 mL), and dried under reduced pressure at 50°C. to give 31 g of Example 9 Ca-PSS resin as a light brown powder.Particle Size: d(0.1)=51 μm; d(0.5)=75 μm; d(0.9)=105 μm. Ca-salt (8.53wt % by titration); Residual Styrene: Not Detected (<0.1 ppm).

Example 10 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.8% Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 1.8% DVB:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added polyvinyl alcohol (10 g),NaCl (10 g), NaNO₂ (0.2 g) and water (1 L). The mixture was stirred andheated to 70° C. for 1 hour to form a slightly turbid solution. In aseparate container, styrene (150 mL), divinylbenzene (3.5 mL, 80%Technical Grade), and benzoyl peroxide (6 g, 98%) were mixed to form ahomogeneous solution of monomers and initiator. The monomer-initiatorsolution was added to the hot aqueous solution and within 1-2 minutes auniform white suspension was achieved with 600 RPM stirring. The mixturewas heated to 91-94° C. for 18 hours, and then filtered while hot usinga coarse fritted funnel. The solid polystyrene beads were suspended inwater (1 L), and heated at 90° C. for 1 hour. The mixture was thenfiltered while hot using a coarse fritted funnel, and the polystyrenebeads were suspended in isopropanol (“IPA”) (1 L), and heated at refluxfor 1 hour. The mixture was then filtered while still hot using a coarsefritted funnel, and dried in a vacuum oven to give 134 g of polystyrenebeads as a white powder. Particle size: d_(v)(0.1)=30 μm; d_(v)(0.5)=40μm; d_(v)(0.9)=60 μm.

Example 10

To a 1 L round bottom flask, equipped with overhead stirrer, N₂ inlet,and a thermocouple was added silver sulfate (0.44 g) and sulfuric acid(98%, 330 mL). The mixture was warmed to 80° C. to dissolve, and thenpolystyrene beads (22 g) were added and the mixture stirred to form asuspension. The mixture was warmed to 100° C. for 2 hours, then pouredinto ice cold 50% aqueous H₂SO₄ (2 kg) The mixture was then diluted to afinal volume of 3.5 L with water and allowed to stand overnight tosettle. The dark supernatant was discarded, and the bead layer filteredusing a coarse fritted funnel. The beads were washed with water untilthe pH of the filtrate was >4, as measured by pH indicator strips. Thewet beads were then suspended in aqueous Ca(OAc)₂ (20% wt, 1 L) andshaken for 24 hours at 37° C., then the mixture was filtered, and thebeads suspended in new aqueous Ca(OAc)₂ (20% wt, 1 L) and shaken againfor 24 hours at 37° C. The beads were then washed successively withwater (2×1 L), 50% ethanol-water (“EtOH-water”) (2×150 mL), 75%EtOH-water (2×150 mL), and 100% EtOH (2×150 mL), and dried under reducedpressure at 50° C. to give 35.5 g of Example 10 Ca-PSS resin as a finelight brown powder. Particle Size: d(0.1)=53 μm; d(0.5)=78 μm;d(0.9)=114 μm. Ca-salt (7.80 wt % by titration); K+ exchange capacity1.6 mEq/g (per BP); Residual Styrene (2.1 ppm).

Example 11 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with2.0% Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 2.0% DVB:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added polyvinyl alcohol (10 g),NaCl (10 g), NaNO₂ (0.2 g) and water (1 L). The mixture was stirred andheated to 70° C. for 1 hour to form a slightly turbid solution. In aseparate container, styrene (75 mL), divinylbenzene (1.9 mL, 80%Technical Grade), and benzoyl peroxide (3 g, 98%) were mixed to form ahomogeneous solution of monomers and initiator. The monomer-initiatorsolution was added to the hot aqueous solution and within 1-2 minutes auniform white suspension was achieved with 600 RPM stirring. The mixturewas heated to 85° C. for 24 hours, and then filtered while hot using acoarse fritted funnel. The solid polystyrene beads were suspended inwater (700 ml), and heated at 85° C. for 1 hour. The mixture was thenfiltered while hot using a coarse fritted funnel, and the polystyrenebeads were suspended in IPA (700 ml), and heated at reflux for 1 hour.The mixture was then filtered while still hot using a coarse frittedfunnel, and dried in a vacuum oven to give 41.9 g of polystyrene beadsas a white powder.

Example 11

To a 1 L round bottom flask, equipped with overhead stirrer, N₂ inlet,and a thermocouple was added silver sulfate (0.4 g) and sulfuric acid(98%, 300 mL). The mixture was warmed to 80° C. to dissolve, and thenpolystyrene beads (20 g) were added and the mixture stirred to form asuspension. The mixture was warmed to 100° C. for 3 h, then poured intoice cold 50% aqueous H₂SO₄ (2 kg). The mixture was then diluted to afinal volume of 5 L with water and allowed to stand overnight to settle.The dark supernatant was discarded, and the bead layer filtered using acoarse fritted funnel. The beads were washed with water until the pH ofthe filtrate was >4, as measured by pH indicator strips. The wet beadswere then suspended in aqueous calcium acetate (“Ca(OAc)₂”) (20% wt, 2L) and shaken for 24 hours at 37° C., then the mixture was filtered, andthe beads suspended in new aqueous Ca(OAc)₂ (20% wt, 2 L) and shakenagain for 24 hours at 37° C. The beads were then washed successivelywith water (4×200 mL), and 100% MeOH (2×1500 mL), and dried underreduced pressure at 50° C. to give 29.8 g of Example 11 Ca-PSS resin asa fine light brown powder. Particle Size: d_(v)(0.1)=32 μm;d_(v)(0.5)=49 μm; d_(v)(0.9)=69 μm (visual microscopy). Ca-salt (8.6%wt/wt by titration); K+ exchange capacity (1.4 mE/g, per BP).

Example 12 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with2.2% Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 2.2% DVB:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added polyvinyl alcohol (10 g),NaCl (10 g), NaNO₂ (0.2 g) and water (1 L). The mixture was stirred andheated to 70° C. for 1 h to form a slightly turbid solution. In aseparate container, styrene (150 mL), divinylbenzene (3.5 mL, 80%Technical Grade), and benzoyl peroxide (6 g, 98%) were mixed to form ahomogeneous solution of monomers and initiator. The monomer-initiatorsolution was added to the hot aqueous solution and within 1-2 minutes auniform white suspension was achieved with 600 RPM stirring. The mixturewas heated to 91-94° C. for 18 h, and then filtered while hot using acoarse fritted funnel. The solid polystyrene beads were suspended inwater (1 L), and heated at 90° C. for 1 h. The mixture was then filteredwhile hot using a coarse fritted funnel, and the polystyrene beads weresuspended in IPA (1 L), and heated at reflux for 1 h. The mixture wasthen filtered while still hot using a coarse fritted funnel, and driedin a vacuum oven to give 134 g of polystyrene beads as a white powder.Particle Size: d_(v)(0.1)=30 μm; d_(v)(0.5)=45 μm; d_(v)(0.9)=70 μm.

Example 12

To a 1 L round bottom flask, equipped with overhead stirrer, N₂ inlet,and a thermocouple was added silver sulfate (0.4 g) and sulfuric acid(98%, 300 mL). The mixture was warmed to 80° C. to dissolve, and thenpolystyrene beads (20 g) were added and the mixture stirred to form asuspension. The mixture was warmed to 90° C. for 1.5 h, then 100° C. for1 h, then poured into ice cold 50% aqueous H₂SO₄ (2 kg) The mixture wasthen diluted to a final volume of 4 L with water and allowed to standovernight to settle. The dark supernatant was discarded, and the beadlayer filtered using a coarse fritted funnel. The beads were washed withwater until the pH of the filtrate was >4, as measured by pH indicatorstrips. The wet beads were then suspended in aqueous Ca(OAc)₂ (20% wt, 1L) and shaken for 24 h at 37° C., then the mixture was filtered, and thebeads suspended in new aqueous Ca(OAc)₂ (20% wt, 1 L) and shaken againfor 24 h at 37° C. The beads were then washed successively with water(2×1 L), 50% EtOH-water (2×150 mL), 75% EtOH-water (2×150 mL), and 100%EtOH 2×150 mL), and dried under reduced pressure at 50° C. to give 36.9g of Example 12 Ca-PSS resin as a fine light brown powder. ParticleSize: d(0.1)=53 μm; d(0.5)=76 μm; d(0.9)=108 μm; Ca-salt (8.3% wt/wt bytitration); K+ exchange capacity (1.3 meq/g per BP); Residual Styrene (6ppm).

Example 13 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with2.08% Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 2.08% DVB:

To round bottom flask equipped with a heating mantle, an overheadstirrer, thermocouple, and N₂ inlet was added polyvinyl alcohol (1 g),NaCl (10 g), NaNO₂ (0.2 g) and water (1 L). The mixture was stirred andheated to 70° C. for 1 hour to dissolve, and then cooled to 20° C. In aseparate container, styrene (147 g), divinylbenzene (3.9 g, 80%Technical Grade), and benzoyl peroxide (6.5 g, 98%) were mixed to form ahomogeneous solution of monomers and initiator. The monomer-initiatorsolution was added to the aqueous solution and homogenized for 5 min at6000 rpm (IKA Ultra-Turrax T50 basic, S50N-G45F). The mixture wasstirred at 300 rpm and heated to 92° C. for 21 hours. The suspension wascooled and filtered using a coarse fritted funnel. The solid polystyrenebeads were washed successively with water (2×350 mL), acetone (2×350mL), and IPA (2×350 mL), and dried in a vacuum oven to give 135 g ofpolystyrene beads as a white powder. Particle size: d(0.1)=6.17 μm;d(0.5)=10.1 μm; d(0.9)=17.1 μm.

Example 13

To a 1 L round bottom flask, equipped with overhead stirrer, N₂ inlet,and a thermocouple was added silver sulfate (0.4 g) and sulfuric acid(98%, 300 mL). The mixture was warmed to 85° C. to dissolve, and thenpolystyrene beads (20 g) were added and the mixture stirred to form asuspension. The mixture was warmed to 100° C. for 3 hours, then pouredinto ice cold 50% aqueous H₂SO₄ (700 mL). The mixture was then dilutedto a final volume of 3000 L with water and filtered using a coarsefritted funnel. The beads were washed with water until the pH of thefiltrate was >4, as measured by pH indicator strips. The wet beads werethen suspended in aqueous Ca(OAc)₂ (20% wt, 1.4 L) and shaken for 24hours at 37° C., then the mixture was filtered, and the beads suspendedin new aqueous Ca(OAc)₂ (20% wt, 1.4 L) and shaken again for 24 hours at20° C. The beads were then washed successively with water (4×200 mL),70% EtOH-water (2×150 mL), and 100% EtOH (2×150 mL), and dried underreduced pressure at 50° C. to give 28.6 g of Example 13 Ca-PSS resin asa light brown powder. The material was sieved using a 270 mesh (53 μmsieve to give a powder with Particle Size: d_(v)(0.1)=2 μm;d_(v)(0.5)=15 μm; d_(v)(0.9)=30 μm. Ca-salt (9.1 wt % by titration); K+exchange capacity (1.46 mE/g, per BP); Residual Styrene: Not Detected(<0.1 ppm).

Example 14 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with2.5% Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 2.5% DVB:

To round bottom flask equipped with a heating mantle, an overheadstirrer, thermocouple, and N₂ inlet was added polyvinyl alcohol (1 g),NaCl (10 g), NaNO₂ (0.2 g) and water (1 L). The mixture was stirred andheated to 70° C. for 1 hour to dissolve, and then cooled to 20° C. In aseparate container, styrene. DVB and (147 g), divinylbenzene (4.7 g, 80%Technical Grade), and benzoyl peroxide (6.5 g, 98%) were mixed to form ahomogeneous solution of monomers and initiator. The monomer-initiatorsolution was added to the aqueous solution and homogenized for 5 minutesat 6000 rpm (IKA Ultra-Turrax T50 basic, S50N-G45F). The mixture wasstirred at 300 rpm and heated to 92° C. for 21 hours. The suspension wascooled and filtered using a coarse fritted funnel. The solid polystyrenebeads were washed successively with water (2×350 mL), acetone (2×350mL), and IPA (2×350 mL), and dried in a vacuum oven to give 133 g ofpolystyrene beads as a white powder. Particle size: d(0.1)=4 μm;d(0.5)=8 μm; d(0.9)=15 μm.

Example 14

To a 1 L round bottom flask, equipped with overhead stirrer, N₂ inlet,and a thermocouple was added silver sulfate (0.4 g) and sulfuric acid(98%, 300 mL). The mixture was warmed to 85° C. to dissolve, and thenpolystyrene beads (20 g) were added and the mixture stirred to form asuspension. The mixture was warmed to 100° C. for 3 hours, then pouredinto ice cold 50% aqueous H₂SO₄ (800 mL) The mixture was then diluted toa final volume of 3000 L with water and filtered using a coarse frittedfunnel. The beads were washed with water until the pH of the filtratewas >4, as measured by pH indicator strips. The wet beads were thensuspended in aqueous Ca(OAc)₂ (20% wt, 1.4 L) and shaken for 24 hours at37° C., then the mixture was filtered, and the beads suspended in newaqueous Ca(OAc), (20% wt, 1.4 L) and shaken again for 24 hours at 20° C.The beads were then washed successively with water (4×200 mL), 70%EtOH-water (2×150 mL), and 100% EtOH (2×150 mL), and dried under reducedpressure at 50° C. to give 30 g of Example 14 Ca-PSS resin as a lightbrown powder. The material was sieved using a 270 mesh (53 μm) sieve togive a powder with Particle Size: d(0.1)=3 μm; d(0.5)=15 μm; d(0.9)=27μm; Ca-salt (9.05 wt % by titration); K+ exchange capacity (1.41 mE/g,per BP); Residual Styrene: Not Detected.

Example 15 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with 4%Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 4% DVB:

To round bottom flask equipped with a heating mantle, an overheadstirrer, thermocouple, and N₂ inlet was added polyvinyl alcohol (1 g),NaCl (10 g), NaNO₂ (0.2 g) and water (1 L). The mixture was stirred andheated to 70° C. for 1 hour to dissolve, and then cooled to 20° C. In aseparate container, styrene (143.4 g), divinylbenzene (7.5 g, 80%Technical Grade), and benzoyl peroxide (6.5 g, 98%) were mixed to form ahomogeneous solution of monomers and initiator. The monomer-initiatorsolution was added to the aqueous solution and homogenized for 5 minutesat 8000 rpm (IKA Ultra-Turrax T50 basic, S50N-G45F). The mixture wasstirred at 300 rpm and heated to 92° C. for 21 hours. The suspension wascooled and filtered using a coarse fritted funnel. The solid polystyrenebeads were washed successively with water (2×350 mL), acetone (2×350mL), and IPA (2×350 mL), and dried in a vacuum oven to give 132 g ofpolystyrene beads as a white powder. Particle size: d_(v)(0.1)=2 μm;d_(v)(0.5)=7 μm; d_(v)(0.9)=11 μm.

Example 15

To a 1 L round bottom flask, equipped with overhead stirrer. N₂ inlet,and a thermocouple was added silver sulfate (0.4 g) and sulfuric acid(98%, 300 mL). The mixture was warmed to 80° C. to dissolve, and thenpolystyrene beads (20 g) were added and the mixture stirred to form asuspension. The mixture was warmed to 100° C. for 3 hours, then pouredinto ice cold 50% aqueous H₂SO₄ (3 kg) The mixture was then diluted to afinal volume of 4 L with water and allowed to stand overnight to settle.The dark supernatant was discarded, and the bead layer filtered using acoarse fritted funnel. The beads were washed with water until the pH ofthe filtrate was >4, as measured by pH indicator strips. The wet beadswere then suspended in aqueous Ca(OAc)₂ (20% wt, 1.4 L) and shaken for24 hours at 37° C., then the mixture was filtered, and the beadssuspended in new aqueous Ca(OAc)₂ (20% wt, 1.4 L) and shaken again for24 hours at 37° C. The beads were then washed successively with water(4×200 mL), 70% EtOH-water (2×150 mL), and 100% EtOH (2×150 mL), anddried under reduced pressure at 50° C. to give 34 g of Example 15 Ca-PSSresin as a light brown powder. Particle Size: d(0.1)=3 μm; d(0.5)=12 μm;d(0.9)=21 μm. Ca-salt (9.05 wt % by titration); K+ exchange capacity(1.32 mE/g, per BP); Residual Styrene (0.1 ppm).

Example 16 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with 8%Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 8% DVB:

To round bottom flask equipped with a heating mantle, an overheadstirrer, thermocouple, and N₂ inlet was added polyvinyl alcohol (1 g),NaCl (10 g), NaNO₂ (0.2 g) and water (1 L). The mixture was stirred andheated to 70° C. for 1 hour to dissolve, and then cooled to 20° C. In aseparate container, styrene (98 g), divinylbenzene (10.7 g, 80%Technical Grade), and benzoyl peroxide (4.5 g, 98%) were mixed to form ahomogeneous solution of monomers and initiator. The monomer-initiatorsolution was added to the aqueous solution and homogenized for 5 min at8000 rpm (IKA Ultra-Turrax T50 basic, S50N-G45F). The mixture wasstirred at 300 rpm and heated to 92° C. for 4 hours, then 85° C.overnight. The suspension was cooled and filtered using a coarse frittedfunnel. The solid polystyrene beads were washed successively with water(2×350 mL), acetone (2×350 mL), and IPA (2×350 mL), and dried in avacuum oven to give 91 g of polystyrene beads as a white powder.Particle size: d_(v)(0.1)=3 μm; d_(v)(0.5)=7 μm; d_(v)(0.9)=11 μm.

Example 16

To a 1 L round bottom flask, equipped with overhead stirrer, N₂ inlet,and a thermocouple was added silver sulfate (0.4 g) and sulfuric acid(98%, 300 mL). The mixture was warmed to 80° C. to dissolve, and thenpolystyrene beads (20 g) were added and the mixture stirred to form asuspension. The mixture was warmed to 100° C. for 3 hours, then pouredinto ice cold 50% aqueous H₂SO₄ (3 kg) The mixture was then diluted to afinal volume of 4 L with water and allowed to stand overnight to settle.The dark supernatant was discarded, and the bead layer filtered using acoarse fritted funnel. The beads were washed with water until the pH ofthe filtrate was >4, as measured by pH indicator strips. The wet beadswere then suspended in aqueous Ca(OAc)₂ (20% wt, 1.4 L) and shaken for24 hours at 37° C., then the mixture was filtered, and the beadssuspended in new aqueous Ca(OAc)₂ (20% wt, 1.4 L) and shaken again for24 hours at 37° C. The beads were then washed successively with water(4×200 mL), 70% EtOH-water (2×150 mL), and 100% EtOH (2×150 mL), anddried under reduced pressure at 50° C. to give 32.4 g of Example 16Ca-PSS resin as a light brown powder. Particle Size: d_(v)(0.1)=2 μm;d_(v)(0.5)=11 μm; d_(v)(0.9)=17 μm. Ca-salt (8.58 wt % by titration); K+exchange capacity (1.43 mE/g, per BP).

Example 17 Preparation of Calcium Polystyrene Sulfonate from SeededPolymerization

Intermediate Polystyrene Seed Particles (2 μm) by DispersionPolymerization:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added styrene (136 mL, used asis), polyvinylpyrrolidone (“PVP”) (12 g, MW 40,000), and anhydrous EtOH(784 mL). The mixture was stirred at 200 rpm and heated to 70° C. toachieve full solution. After 30 min, AIBN (1.2 g) dissolved in anhydrousEtOH (224 mL) was added to the solution. The mixture was stirred at 70°C. for 24 hours, then cooled to 20° C. The PS seed particles wereisolated by centrifugation at 5300 G for 10 minutes, the supernatant wasdiscarded and the solid suspended in EtOH (2×150 mL) by shaking for 15minutes, and the solid isolated by centrifugation at 5300 G for 10minutes. The solid was dried under reduced pressure at 50° C. to give73.9 g of seed particles as a white powder. d_(v)(0.1)=0.6 μm;d_(v)(0.5)=2 μm; d_(v)(0.9)=3 μm.

Intermediate PS Beads from Seeded Polymerization:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added PS seed particles (5 g)and sodium dodecyl sulfate aqueous solution (0.25% (w/w), 500 mL) andthe mixture was stirred overnight (35° C., 120 rpm). Then, amonomer-initiator solution containing BPO (1.5 g), styrene (50 mL),divinylbenzene (3.62 g, 6.4% based on styrene) (divinylbenzene waspurified by passing 10 g of technical grade DVB through 10 g of basicalumina) was added to the mixture containing PS seeds. The mixture washomogenized (VWR homogenizer, model VDI 25) at 17500 rpm for 30 minutes.The mixture was stirred overnight (35° C. at 120 rpm) to swell the seedparticles. The swelling was monitored by optical microscopy. After 20hours, the mixture was homogenized again (VWR homogenizer, model VDI25). Separately, PVP (2.5 g, MW 350,000) was dissolved in deionizedwater (250 mL), and added to the swollen seed mixture. The mixture wasstirred at 400 rpm and heated to 75° C. for 24 hours, then cooled to 20°C. The PS beads were isolated by centrifugation at 5300 G for 10 min.The solid was suspended in water (200 mL) for 10 minutes by shaking andisolated by centrifugation at 5300 G for 10 minutes, the solid wassuspended in EtOH (2×150 mL) for 15 minutes by shaking, and isolated bycentrifugation at 5300 G for 10 minutes, and the supernatant discarded.The solid was dried under reduced pressure at 50° C. to give 32.1 g ofbead particles as a white powder.

Example 17

To a round bottom flask, equipped with overhead stirrer, N₂ inlet, and athermocouple was added silver sulfate (0.4 g) and sulfuric acid (98%,300 mL). The mixture was warmed to 80° C. to dissolve, and thenintermediate PS beads from seeded polymerization (20 g) were added andthe mixture stirred to form a suspension. The mixture was warmed to 100°C. for 3 hours, then poured into ice cold 50% aqueous H₂SO₄ (2 kg). Themixture was then diluted to a final volume of 5 L with water and allowedto stand overnight to settle. The dark supernatant was discarded, andthe bead layer was isolated by centrifugation at 3400 G for 10 minutes;the supernatant was discarded and the beads were washed with water untilthe pH of the filtrate was >4, as measured by pH indicator strips. Thewet beads were then suspended in aqueous Ca(OAc)₂ (20% wt, 2 L) andshaken for 24 hours at 37° C., then the beads were isolated bycentrifugation at 3400 G for 10 minutes. The supernatant was discarded,and the beads suspended in new aqueous Ca(OAc)₂ (20% wt, 2 L) and shakenagain for 24 hours at 37° C. The beads were isolated by centrifugationat 3400 G for 10 minutes. The beads were washed and centrifugedsuccessively with MeOH (2×150 mL), and dried under reduced pressure at50° C. to give 36.9 g of Example 17 Ca-PSS resin. A portion of the beads(19 g) was further washed by successive suspension and centrifugation at3400×g with water (700 mL), 70% EtOH (2×250 mL), and 100% EtOH (2×250mL). The isolated solid was then dried under reduced pressure at 50° C.to give 18.8 g of Example 17 as a light brown powder. Particle Size:d_(v)(0.1)=1 nm; d_(v)(0.5)=6 μm; d_(v)(0.9)=10 μm. Ca-salt (7.55 wt %by titration); K+ exchange capacity 1.0 mEq/g (per BP); Residual Styrene0.4 ppm.

Example 18 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with2.0% Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 2.0% DVB:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added polyvinyl alcohol (10 g),NaCl (10 g), NaNO₂ (0.2 g) and water (1 L). The mixture was stirred andheated to 70° C. for 1 hour to form a slightly turbid solution. In aseparate container, styrene (150 mL), divinylbenzene (3.8 mL, 80%Technical Grade), and benzoyl peroxide (6 g, 98%) were mixed to form ahomogeneous solution of monomers and initiator. The monomer-initiatorsolution was added to the hot aqueous solution and within 1-2 minutes auniform white suspension was achieved with 600 RPM stirring. The mixturewas heated to 91-94° C. for 18 hours, and then filtered while hot usinga coarse fritted funnel. The solid polystyrene beads were suspended inwater (1 L), and heated at 90° C. for 1 hour. The mixture was thenfiltered while hot using a coarse fritted funnel, and the polystyrenebeads were suspended in IPA (1 L), and heated at reflux for 1 h. Themixture was then filtered while still hot using a coarse fritted funnel,and dried in a vacuum oven to give 136 g of polystyrene beads as a whitepowder. Particle Size: d_(v)(0.1)=30 μm; d_(v)(0.5)=40 μm; d_(v)(0.9)=60μm.

Example 18

To a 1 L round bottom flask, equipped with overhead stirrer, N₂ inlet,and a thermocouple was added silver sulfate (0.4 g) and sulfuric acid(98%, 300 mL). The mixture was warmed to 80° C. to dissolve, and thenpolystyrene beads (20 g) were added and the mixture stirred to form asuspension. The mixture was warmed to 100° C. for 3 hours, then pouredinto ice cold 50% aqueous H₂SO₄ (2 kg) The mixture was then diluted to afinal volume of 3.5 L with water and allowed to stand overnight tosettle. The dark supernatant was discarded, and the bead layer filteredusing a coarse fritted funnel. The beads were washed with water untilthe pH of the filtrate was >4, as measured by pH indicator strips. Thewet beads were then suspended in aqueous Ca(OAc)₂ (20% wt, 1 L) andshaken for 24 hours at 37° C., then the mixture was filtered, and thebeads suspended in new aqueous Ca(OAc)₂ (20% wt, 1 L) and shaken againfor 24 hours at 37° C. The beads were then washed successively withwater (4×200 mL), 70% EtOH-water (2×150 mL), and 100% EtOH (2×150 mL),and dried under reduced pressure at 50° C. to give 35.7 g of Example 18Ca-PSS resin as a fine light brown powder. Particle Size: d_(v)(0.1)=57μm; d_(v)(0.5)=80 μm; d_(v)(0.9)=110 μm.

Example 19 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.8% Divinylbenzene (DVB)

Example 19 was prepared from 40 g crosslinked (1.8%) polystyrenesulfonate beads using the procedures described in Example 10 to give69.4 g of Example 19 as a light brown powder: particle size 30-130 μm(visual microscopy). Residual Styrene: Not Detected.

Example 20 Preparation of Calcium Polystyrene Sulfonate from SeededPolymerization

Intermediate Polystyrene Seed Particles (2 μm) by DispersionPolymerization:

Seeds were prepared following the procedures described in Example 17.

Intermediate PS Beads from Seeded Polymerization:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added PS seed particles (5 g),sodium dodecyl sulfate aqueous solution (0.25% (w/w), 500 mL). Themixture was stirred overnight (35° C., 120 rpm). Then, amonomer-initiator solution containing BPO (1.5 g), styrene (50 mL),divinylbenzene (0.91 g, 1.8% based on styrene) (divinylbenzene waspurified by passing 10 g of technical grade DVB through 10 g of basicalumina) was added to the mixture containing PS seeds. The mixture washomogenized (IKA homogenizer, model T50 Digital) at 2000 rpm for 30minutes. The mixture was stirred overnight (35° C. at 120 rpm) to swellthe seed particles. The swelling was monitored by optical microscopy.After 20 hours, the mixture was homogenized again at 2000 rpm for 30minutes (IKA homogenizer, model T50 Digital). Separately, PVP (2.5 g, MW350,000) was dissolved in deionized water (250 mL), and added to theswollen seed mixture. The mixture was stirred at 400 rpm and heated to75° C. for 24 hours, then cooled to 20° C. The PS beads were isolated bycentrifugation at 5300 G for 10 minutes. The solid was suspended in MeOH(200 mL) for 15 min by shaking, and isolated by centrifugation at 5300 Gfor 10 minutes, and the supernatant discarded. The solid was dried underreduced pressure at 50° C. to give 27.74 g of bead particles as a whitepowder. Approximate particle size range 6-8 μm by visual microscopy.

Example 20

To a round bottom flask, equipped with overhead stirrer, N₂ inlet, and athermocouple was added silver sulfate (0.4 g) and sulfuric acid (98%,300 mL). The mixture was warmed to 80° C. to dissolve, and thenintermediate PS beads from seeded polymerization (20 g) were added andthe mixture stirred to form a suspension. The mixture was warmed to 100°C. for 3 hours, then poured into ice cold 50% aqueous H₂SO₄ (2 kg). Themixture was then diluted to a final volume of 5 L with water and allowedto stand overnight to settle. The dark supernatant was discarded, andthe bead layer was isolated by centrifugation at 3400 G for 10 minutes;the supernatant was discarded and the beads were washed with water untilthe pH of the filtrate was >4, as measured by pH indicator strips. Thewet beads were then suspended in aqueous Ca(OAc)₂ (20% wt, 2 L) andshaken for 24 hours at 37° C., then the beads were isolated bycentrifugation at 3400 G for 10 minutes. The supernatant was discarded,and the beads suspended in new aqueous Ca(OAc)₂ (20% wt, 2 L) and shakenagain for 24 hours at 37° C. The beads were isolated by centrifugationat 3400 G for 10 minutes. The beads were washed and centrifugedsuccessively with water (200 mL) and 70% MeOH (2×150 mL), and driedunder reduced pressure at 50° C. to give 33.2 g of Example 20 Ca-PSSresin as a dark brown chunks. The beads were suspended and centrifugedsuccessively with water (700 mL), 70% EtOH (500 mL), and 100% IPA (200mL) and dried under reduced pressure at 50° C. to give 27.8 g of Example20 Ca-PSS resin as a dark brown chunks. A portion of the beads weresuspended and centrifuged successively with water (2×2 L), followed by70% EtOH (500 mL) and 100% EtOH (500 mL). The material was dried underreduced pressure (50° C.) to give 16.3 g of Example 20 Ca-PSS resin as alight brown powder: particle size d_(v)(0.1)=4 μm; d_(v)(0.5)=7 μm;d_(v)(0.9)=12 μm; Ca-salt (7.53 wt % by titration); K⁺ exchange capacity1.4 mEq/g (per BP); Residual Styrene 0.09 ppm.

Example 21 Preparation of Calcium Polystyrene Sulfonate from SeededPolymerization

Intermediate Polystyrene Seed Particles (4 μm) by DispersionPolymerization:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added styrene (68 mL, used asis), Polyvinylpyrrolidone, PVP, (6 g, MW 40,000), and IPA (392 mL). Themixture was stirred at 200 rpm and heated to 70° C. to achieve fullsolution. After 30 minutes, Azobisisobutyronitrile (“AIBN”) (0.6 g)dissolved in IPA (112 mL) was added to the solution. The mixture wasstirred at 70° C. for 24 hours, then cooled to 20° C. The PS seedparticles were isolated by centrifugation at 5300 G for 10 minutes, thesupernatant was discarded and the solid suspended in EtOH (150 mL) byshaking for 15 minutes, and the solid isolated by centrifugation at 5300G for 10 minutes. The solid was dried under reduced pressure at 50° C.to give 55.28 g of seed particles as a white powder. Particle sized_(v)(0.1)=2 μm; d_(v)(0.5)=4 μm; d_(v)(0.9)=6 μm.

Intermediate PS Beads from Seeded Polymerization:

To a jacketed Morton style cylindrical vessel equipped with an overheadstirrer, thermocouple, and N₂ inlet was added PS seed particles (3 g),sodium dodecyl sulfate aqueous solution (0.25% (w/w), 300 mL). Themixture was stirred overnight (35° C., 120 rpm). Then, amonomer-initiator solution containing BPO (1.5 g), styrene (30 mL),divinylbenzene (0.54 g, 1.8% based on styrene) (divinylbenzene waspurified by passing 10 g of technical grade DVB through 10 g of basicalumina) was added to the mixture containing PS seeds. The mixture washomogenized (IKA homogenizer, model T50 Digital) at 2000 rpm for 30minutes. The mixture was stirred overnight (35° C. at 120 rpm) to swellthe seed particles. The swelling was monitored by optical microscopy.Separately. PVP (1.5 g. MW 350,000) was dissolved in deionized water(150 mL), and added to the swollen seed mixture. The mixture was stirredat 400 rpm and heated to 75° C. for 24 hours, then cooled to 20° C. ThePS beads were isolated by centrifugation at 5300 G for 10 minutes. Thesolid was suspended in water (200 mL) for 10 minutes by shaking andisolated by centrifugation at 5300 G for 10 minutes. Then the solid wassuspended in EtOH (2×150 mL) for 15 minutes by shaking, and isolated bycentrifugation at 5300 G for 10 minutes, and the supernatant discarded.The solid was dried under reduced pressure at 50° C. to give 16 g ofbead particles as a white powder.

Example 21

To a round bottom flask, equipped with overhead stirrer, N₂ inlet, and athermocouple was added silver sulfate (0.32 g) and sulfuric acid (98%,240 mL). The mixture was warmed to 80° C. to dissolve, and thenintermediate PS beads from seeded polymerization (16 g) were added andthe mixture stirred to form a suspension. The mixture was warmed to 100°C. for 3 hours, then poured into ice cold 50% aqueous H₂SO₄ (2 kg). Themixture was then diluted to a final volume of 5 L with water and allowedto stand overnight to settle. The dark supernatant was discarded, andthe bead layer was isolated by centrifugation at 3400 G for 10 minutes;the supernatant was discarded and the beads were washed with water untilthe pH of the filtrate was >4, as measured by pH indicator strips. Thewet beads were then suspended in aqueous Ca(OAc)₂ (20% wt, 1 L) andshaken for 24 hours at 37° C., then the beads were isolated bycentrifugation at 3400 G for 10 minutes. The supernatant was discarded,and the beads suspended in new aqueous Ca(OAc)₂ (20% wt, 1 L) and shakenagain for 24 hours at 37° C. The beads were isolated by centrifugationat 3400×g for 10 min. The beads were suspended and centrifugedsuccessively with water (200 mL), 70% EtOH (350 mL), 100% EtOH (350 mL),and dried under reduced pressure.

A portion of material (19.5 g) was suspended in water (2000 mL) byshaking at 150 rpm overnight, and isolated by centrifugation at 3400 Gfor 10 min. The beads were washed again with water (2000 mL) andcentrifuged successively with 70% EtOH (2×250 mL), and 100% EtOH (2×250mL), dried under reduced pressure at 50° C. to give Example 21 as alight brown powder. Ca-salt (8.56 wt % by titration); Residual Styrene0.21 ppm.

Example 22 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS), ≦43 μmParticle Size 8% Divinylbenzene (DVB)

Approximately 15 g of Ionex Ca-PSS (Phaex Polymers, India), BritishPharmacopeia (BP) grade, was deposited onto a 320 mesh sieve (43 μm poresize) and mechanically agitated on an orbital shaker for approximately30 minutes, and the sieved fraction (solids ≦43 μm) was collected(approximately 3 g). Particle size d_(v)(0.1)=9 μm; d_(v)(0.5)=30 μm;d_(v)(0.9)=60 μm; Ca-salt (8.69 wt % by titration); K+ exchange capacity1.35 mEq/g (per BP); Residual Styrene 0.2 ppm.

Example 23 Preparation of Sodium Polystyrene Sulfonate (Ca-PSS) with 8%Divinylbenzene (DVB)

Approximately 20 g of an aqueous suspension of Na SPS (8% DVB) in awater/sorbitol suspension (Carolina Medical Products) was deposited ontoa sintered glass funnel and washed several times with DI water to removesorbitol, and then dried to afford a tan-colored solid.

Example 24 Preparation of Insoluble Cross-Linked (Calcium2-Fluoroacrylate)-Divinylbenzene-1,7-Octadiene Copolymer

In an appropriately sized reactor with appropriate stirring and otherequipment, a mixture of organic phase of monomers is prepared by mixingmethyl 2-fluoroacrylate, 1,7-octadiene, and divinylbenzene in a moleratio of about 120:1:1, respectively. Approximately one part of lauroylperoxide is added as an initiator of the polymerization reaction. Astabilizing aqueous phase is prepared from water, polyvinyl alcohol,phosphates, sodium chloride, and sodium nitrite. The aqueous and monomerphases are mixed together under nitrogen at atmospheric pressure, whilemaintaining the temperature below 30° C. The reaction mixture isgradually heated while stirring continuously. Once the polymerizationreaction starts, the temperature of the reaction mixture is allowed torise to a maximum of 95° C.

After completion of the polymerization reaction, the reaction mixture iscooled and the aqueous phase is removed. Water is added, the mixture isstirred, and the solid material is isolated by filtration. The solid isthen washed with water to yield a crosslinked (methyl2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer. The (methyl2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer is hydrolyzedwith an excess of aqueous sodium hydroxide solution at 90° C. for 24hours to yield (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadienecopolymer. After hydrolysis, the solid is filtered and washed withwater. The (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadienecopolymer is exposed at room temperature to an excess of aqueous calciumchloride solution to yield insoluble cross-linked (calcium2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer. After thecalcium ion exchange, the product is washed with water and dried.

Example 25 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) from 30Micron Monodisperse Polystyrene Beads

Example 25 was prepared from 20 g polystyrene beads (Amberchrom™ XT30;obtained from Octochemstore.com), using the procedures described inExample 7 to give Example 25 (29.6 g) as a brown powder. Particle size:dv(0.1)=25 μm; dv(0.5)=34 μm; dv(0.9)=48 μm.

Example 26 Procedure for Tactile Testing

Tactile Testing Experiment #1.

Tactile testing samples were prepared by suspending 2.1 g of drypolystyrene sulfonate resin powder (calcium and or sodium forms) in DIwater (15 mL) at 20° C. in amber bottles. The mixtures were shakenvigorously for 1 min by hand, and then allowed to stand overnight.Immediately prior to dispensing samples to test subjects, the vials wereagitated using a bench top vortex mixer for approximately 20 seconds.Test subjects washed their hands with soap and water before beginning. Atactile test sample of 150 μL was dispensed onto the thenar eminence ofone hand, and the test subjects were instructed to rub test samplebetween the thenar eminence of both hands. Test subjects rated theirexperience on two sensations: grittiness (Table 1), and tackiness (Table2). Sensations were rated from 1-5 with 1=no sensation and 5=strongsensation. After each sample, test subjects washed their hands with soapand water.

TABLE 1 GRITTINESS DATA FROM TACTILE TESTING EXPERIMENT #1. Example # 22N/A¹ 12 11 10 9 4 23 Resin ID 1 2 3 4 5 6 7 8 Crosslinking ~8% ~8% 2.2%2.0% 1.8% 1.6% 2.0% ~8% Particle size 45 μm N/A 76 μm 44 μm 77 μm 75 μm120 μm 69 μm (Dv50) morphology Shard Shard Sphere Sphere Sphere SphereSphere Shard Subject ID Grittiness Subject 1 4 5 4 2 1 3 5 5 Subject 2 32 2 1 1 2 3 3 Subject 3 5 4 2 1 2 2 4 5 Subject 4 3 3 3 1 2 2 4 4Subject 5 4 4 1 1 2 1 2 4 Subject 6 4 3 3 1 2 2 4 4 Subject 7 3 3 1 1 11 3 2 Subject 8 2 3 2 1 1 2 2 3 Subject 9 4 4 4 1 1 1 3 4 Subject 10 3 32 1 1 2 4 5 Subject 11 5 2 1 1 2 2 3 3 Subject 12 4 2 1 1 1 2 3 3Subject 13 5 4 3 2 1 1 1 5 Subject 14 5 4 2 2 1 1 3 4 Subject 15 5 4 2 21 1 4 5 Subject 16 3 3 2 1 2 1 3 4 Subject 17 5 2 2 1 1 2 3 5 Subject 185 4 3 2 1 2 4 5 Average 4.0 3.3 2.2 1.3 1.3 1.7 3.2 4.1 Std Dev 1.0 0.90.9 0.5 0.5 0.6 0.9 0.9 total 72 59 40 23 24 30 58 73 ¹RESONIUMCALCIUM ®, Ca-PSS, Sanofi-Aventis

TABLE 2 TACKINESS DATA FROM TACTILE TESTING EXPERIMENT #1. Example # 22N/A¹ 12 11 10 9 4 23 Resin ID 1 2 3 4 5 6 7 8 Crosslinking ~8% ~8% 2.2%2.0% 1.8% 1.6% 2.0% ~8% Particle size 45 μm N/A 76 μm 44 μm 77 μm 75 μm120 μm 69 μm (Dv50) Morphology Shard Shard Sphere Sphere Sphere SphereSphere shard Subject ID Tackiness Subject 1 1 1 1 1 1 1 1 1 Subject 2 11 1 1 1 2 3 1 Subject 3 1 2 1 1 2 2 1 1 Subject 4 1 1 1 2 1 1 1 1Subject 5 1 1 1 1 1 2 1 1 Subject 6 1 1 1 1 1 2 1 1 Subject 7 2 1 2 2 33 2 2 Subject 8 1 1 2 3 4 3 2 1 Subject 9 1 1 1 2 3 4 3 1 Subject 10 1 21 3 2 3 1 2 Subject 11 1 1 1 1 1 1 1 1 Subject 12 1 1 2 2 1 3 1 2Subject 13 1 1 1 2 3 3 3 1 Subject 14 3 2 2 3 2 1 2 3 Subject 15 1 1 1 15 5 1 1 Subject 16 1 1 1 1 1 2 1 1 Subject 17 3 2 2 1 2 3 3 3 Subject 181 1 1 1 3 3 2 2 Average 1.3 1.2 1.3 1.6 2.1 2.4 1.7 1.4 Std Dev 0.7 0.40.4 0.8 1.2 1.1 0.8 0.7 total 23 22 23 29 37 44 30 26 ¹RESONIUMCALCIUM ®, Ca-PSS, Sanofi-Aventis

Tactile Testing Experiment #2.

Tactile testing samples were prepared by suspending 3 g of drypolystyrene sulfonate resin powder (Calcium and or Sodium forms) in DIwater (15 mL) at 20° C. in amber bottles. The mixtures were shakenvigorously for 1 minute by hand, and then allowed to stand overnight.Immediately prior to dispensing samples to test subjects, the vials wereagitated using a bench top vortex mixer for approximately 20 seconds.Test subjects washed their hands with soap and water before beginning. Atactile test sample of 150 μL was dispensed onto the thenar eminence ofone hand, and the test subjects were instructed to rub the test samplebetween the thenar eminence of both hands. Test subjects rated theirexperience on two sensations: grittiness (Table 3) and tackiness (Table4). Sensations were rated from 1-5 with 1=low sensation and 5=highsensation. After each sample, test subjects washed their hands with soapand water.

TABLE 3 GRITTINESS DATA FROM TACTILE TESTING EXPERIMENT #2 Example #N/A¹ 4 13 14 15 16 17 18 19 22 25 11 Crosslinking N/A 2.0% 2.08% 2.5%4.0% 8.0% 6.5% 2.0% 1.8% N/A N/A 2.0% Particle size N/A 120 μm 13 μm 14μm 12 μm 11 μm 7 μm 81 μm N/A 31 μm N/A 44 μm (Dv50) Morphology ShardsSphere Sphere Sphere Sphere Sphere Sphere Sphere Sphere Shards SphereSphere Resin ID 1 2 3 4 5 6 7 8 9 10 11 12 Subject ID Grittiness Subject1 5 5 2 3 3 2 1 4 3 4 4 4 Subject 2 2 3 1 1 1 2 1 2 3 1 2 1 Subject 3 21 1 1 2 1 2 1 1 3 2 1 Subject 4 4 3 2 3 2 1 2 1 3 1 2 1 Subject 5 4 3 11 2 2 2 1 3 1 2 2 Subject 6 5 3 1 2 2 2 1 1 1 3 1 3 Subject 7 4 5 1 1 23 1 1 2 3 2 1 Subject 8 4 5 1 2 5 3 3 4 2 2 2 2 Subject 9 4 2 2 2 1 1 11 1 3 3 2 Subject 10 4 3 1 3 2 2 3 1 4 1 1 3 Subject 11 3 2 1 2 1 1 1 11 1 1 2 Subject 12 4 3 1 1 2 2 3 1 3 3 3 2 Subject 13 5 4 2 2 1 2 3 3 34 4 2 Average 3.8 3.2 1.3 1.8 2.0 1.8 1.8 1.7 2.3 2.3 2.2 2.0 Std Dev1.0 1.2 0.5 0.8 1.1 0.7 0.9 1.2 1.0 1.2 1.0 0.9 total 50 42 17 24 26 2424 22 30 30 29 26 ¹RESONIUM CALCIUM ®, Ca-PSS, Sanofi-Aventis

TABLE 4 TACKINESS DATA FROM TACTILE TESTING EXPERIMENT #2 Example # N/A¹4 13 14 15 16 17 18 19 22 25 11 Crosslinking N/A 2.0% 2.08% 2.5% 4.0%8.0% 6.5% 2.0% 1.8% N/A N/A 2.0% Particle size N/A 120 μm 13 μm 14 μm 12μm 11 μm 7 μm 81 μm N/A 31 μm N/A 44 μm (Dv50) Morphology Shards SphereSphere Sphere Sphere Sphere Sphere Sphere Sphere Shards Sphere SphereResin ID 1 2 3 4 5 6 7 8 9 10 11 12 Subject ID Grittiness Subject 1 1 11 1 1 1 1 1 1 1 1 1 Subject 2 1 1 2 1 1 1 2 2 1 1 1 2 Subject 3 1 3 3 32 1 1 5 2 1 1 2 Subject 4 1 4 2 1 1 1 1 2 4 1 2 1 Subject 5 1 1 2 2 2 12 2 2 1 2 2 Subject 6 1 1 4 3 3 2 4 4 5 1 4 3 Subject 7 1 1 2 1 1 1 1 22 1 1 1 Subject 8 1 1 3 3 1 2 2 2 2 1 3 3 Subject 9 1 2 3 2 2 1 2 3 4 12 3 Subject 10 1 2 3 4 1 1 2 3 4 1 1 2 Subject 11 1 1 1 1 1 1 1 2 3 1 11 Subject 12 2 1 2 3 3 2 2 3 2 1 4 3 Subject 13 1 2 2 2 1 1 2 3 3 2 1 2Average 1.1 1.6 2.3 2.1 1.5 1.2 1.8 2.6 2.7 1.1 1.8 2.0 Std Dev 0.3 0.90.8 1.0 0.7 0.4 0.8 1.0 1.2 0.3 1.1 0.8 total 14 21 30 27 20 16 23 34 3514 24 26 ¹RESONIUM CALCIUM ®, Ca-PSS, Sanofi-Aventis

Example 27 Measurements of Swelling Ratio of the Calcium PolystyreneSulfonate Resin

The swelling ratio was measured by centrifugation method using thefollowing procedure: accurately weigh approximately 1 g of calciumpolystyrene sulfonate (Ca-PSS) resin into a 50 mL pre-weighed centrifugetube. Add approximately 10-15 mL of deionized water (or 0.9% salinesolution) to immerse the resin, and shake for a minimum of 30 minutes.Centrifuge at relative centrifuge force (RCF) of 2000×g or 2500×g for 30minutes and carefully remove the supernatant. Determine the wet sampleweight and calculate the ratio between the wet sample weight versus thedry sample weight. The swelling ratio of Ca-PSS is correlated to thepercentage of DVB cross-linking. There was no significant differencebetween swelling ratios measured in water versus those determined in0.9% saline when the % DVB cross-linking was above 1.0% (FIG. 1 andTable 1).

Example 28 Particle Size Analysis of Calcium and Sodium PolystyreneSulfonate Resin

Particle size was measured by laser diffraction using a MalvernMastersizer 2000. Samples were introduced as suspensions in DI waterinto a hydro2000S sampler, sonicated if necessary to break downagglomeration, and allowed 5-10 minutes circulation for equilibrationprior to measurements. Results are presented in FIG. 11 (FIG. 11).

TABLE 5 SWELLING RATIO COMPARISON IN WATER AND 0.9% SALINE Swellingratio Swelling ratio in Water in 0.9% Saline CA-PSS resin (RCF = 2000 ×g) (RCF = 2000 × g) Phaex SC40, BP grade; 8% DVB 2.18 2.26 cross-linking¹ Phaex SC47, JP grade; 8% cross- 2.25 2.27 linking ² SKK Argamate89.29% powder; 2.11 2.11 8% cross-linking ³ Example 1; 8% DVBcross-linking 2.10 2.08 Example 2; 4% DVB cross-linking 2.92 2.82Example 3; 2% DVB cross-linking 4.03 3.72 Example 8; 1.12% DVB cross-7.87 7.80 linking Example 7; 0.96% DVB cross- 9.08 8.11 linking ¹Ca-PSS, British Pharmacopeia (BP) grade, manufactured by Phaex PolymersPVT LTD, Maharashtra, India; ² Ca-PSS, Japanese Pharmacopeia (JP) grade,Phaex Polymers PVT LTD, Maharashtra, India; ³ Ca-PSS, JP grade,manufactured by Sanwa Kagaku Kenkyusho Co., Ltd., Japan.

Example 29 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.8% Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 1.8% DVB:

To a jacketed cylindrical vessel equipped with an overhead stirrer,thermocouple, and N₂ inlet, was added polyvinyl alcohol (0.1 kg), NaCl(1.0 kg), NaNO₂ (0.02 kg) and water (100 kg). The mixture was stirredand heated to 85° C. to dissolve solids, then cooled to 25° C. To aseparate vessel equipped with an overhead stirrer and N₂ inlet was addedstyrene (14.7 kg), divinylbenzene (0.34 kg, 80% Technical Grade), andbenzoyl peroxide (0.85 kg, 75%, stabilized with water), and the mixturewas agitated to combine monomers and initiator. The aqueous and monomerliquids were then mixed in 4 portions (˜25-30 L aqueous, ˜5 L monomer)and homogenized using both a steel pitched blade agitator (600-800 RPM),and by a high mixer (IKA T-50 Ultra Turrax, 3000 RPM). The resultingmixtures were transferred to a jacketed cylindrical vessel equipped withan overhead stirrer, thermocouple, and N₂ inlet, and heated to 92° C.for 16 hours, and then cooled to 45° C. for isolation.

The suspension of polystyrene beads was filtered, and the beads werere-suspended in water (70 kg), agitated and heated to 80° C. for 20minutes, then filtered. The beads were re-suspended in 2-propanol (55kg), agitated and heated to 75° C. for 20 minutes, then filtered, anddried under vacuum to give 11 kg of polystyrene beads as a white powderwhich was used in the next step without further purification.

Example 29

To a jacketed cylindrical vessel equipped with an overhead stirrer,thermocouple and N₂ inlet, was added Polystyrene beads (7 kg) andsulfuric acid (98%, 156 kg). The mixture was agitated to form asuspension and warmed to 100-105° C. for 16 hours. The dark mixture wascooled to 45° C., and transferred slowly into cold water (90 kg). Themixture was filtered, and the sulfonated beads were repeatedly washed asa slurry with water at ˜50° C., and filtered until the effluentcontained <0.05 M sulfuric acid. The beads were washed with aqueouscalcium acetate solution (34 kg water, 8.4 kg Ca(OAc)₂) at 50° C.,agitated for 2 hours, then filtered. The beads were washed again withaqueous calcium acetate solution (34 kg water, 8.4 kg Ca(OAc)₂) at 50°C., agitated for 2 hours, and filtered. The beads were washed with wateruntil the calcium content in the effluent was <1000 ppm. The filter cakewas then dried under vacuum to give 12.76 kg of Example 29 as a brownsolid. Particle Size: d(0.1)=13 μm; d(0.5)=29 μm; d(0.9)=52 μm. Ca-salt8.8 wt % (dry basis, by titration); K+ exchange capacity 1.3 mEq/g (perBP, dry basis); residual styrene <1 ppm; water content 5.6% (KarlFisher); swelling ratio 5.7 (dry basis).

Example 30 Preparation of Sodium Polystyrene Sulfonate (Na-PSS) with1.8% Divinylbenzene (DVB)

To a jacketed vessel equipped with an overhead stirrer, thermocouple,and N₂ inlet, was added Ag₂SO₄ (2 g) and conc. H₂SO₄ (1050 mL). Themixture was warmed to 80° C. to dissolve. Intermediate polystyrenebeads, prepared according to Example 29 (100 g), were added and thesuspension warmed to 100° C. for 4 hours. The mixture was cooled to 60°C., and an equal volume of 30% aqueous H₂SO₄ (1050 mL) was slowly addedto the mixture keeping the temperature below 85° C. The mixture was thenfiltered. A portion (approximately ⅓) of this filter cake was repeatedlywashed and filtered as a slurry with water at ˜50° C., until theeffluent pH >4. Then, the filter cake was washed on the filter with IPA(2×150 mL). The beads were suspended in aqueous NaOH (200 mL water, 2 gNaOH) and agitated for 2 hours, then filtered. The material was thensuspended again in aqueous NaOH (200 mL water, 2 g NaOH) and agitatedfor 2 hours, then filtered. The material was then washed successivelywith hot water (3×250 mL), IPA (2×75 mL), and Ethanol (50 mL). The beadswere then dried in a vacuum oven at 50° C. to give 17.2 g Example 30 asa brown solid. Na-salt 8.9% by weight; particle size in water 20-135 μm(visual microscopy).

Example 31 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.8% Divinylbenzene (DVB)

A portion (approximately ⅓) of sulfonated resin from Example 30, wasrepeatedly washed and filtered as a slurry with water at ˜50° C., untilthe effluent pH >4. Then, the filter cake was washed on the filter withIPA (2×150 mL). The beads were then suspended in aqueous calcium acetatesolution (180 g water, 20 g Ca(OAc)₂) at ambient temperature, agitatedfor 2 hours, then filtered. The beads were again suspended in aqueouscalcium acetate solution (180 g water, 20 g Ca(OAc)₂) at ambienttemperature, agitated for 2 hours, then filtered. The beads were washedrepeatedly with water to remove soluble calcium. The beads were thenwashed with IPA (2×75 mL), and ethanol (50 mL). The beads were thendried in a vacuum oven at 50° C. to give 16.7 g of Example 31 as a brownsolid. Ca-salt 7.45% by weight; particle size in water 12-94 μm (visualmicroscopy).

Example 32 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.8% Divinylbenzene (DVB)

Intermediate Polystyrene Beads at 1.8% DVB:

To a jacketed cylindrical vessel equipped with an overhead stirrer,thermocouple, and N₂ inlet, was added polyvinyl alcohol (0.51 kg), NaCl(5.1 kg), NaNO₂ (0.10 kg) and water (470 kg). The mixture was stirredand heated to 75° C. to form a slightly turbid solution, then cooled to25° C. To a separate jacketed cylindrical vessel equipped with anoverhead stirrer, thermocouple, and N₂ inlet, was added styrene (75 kg),divinylbenzene (1.8 kg, 80% Technical Grade), and benzoyl peroxide (4.3kg, 75%, stabilized with water), and the mixture was agitated to combinemonomers and initiator. The monomer-initiator mixture was added to thevessel containing the aqueous solution and agitated for 0.5 hours toform a coarse suspension. This coarse suspension was then homogenized bypumping the liquid twice through a high shear mixer. The resultinghomogenized mixture was heated to 92° C. for 5 hours, and then cooled to20-30° C. for isolation.

The suspension of polystyrene beads was partitioned bycentrifugation-decantation to remove small particles, and to wash thebeads. The final slurry was isolated by filtration, or centrifugation,and dried under vacuum to give 55 kg of polystyrene beads as a whitepowder. Particle size: d(0.1)>5 μm; d(0.9)=<40 μm.

Example 32

To a jacketed cylindrical vessel equipped with an overhead stirrer,thermocouple, and N₂ inlet, was added Polystyrene beads (15 kg), andsulfuric acid (98%, 345 kg). The mixture was stirred to form asuspension then warmed to 100-105° C. for 3.5-4 hours. The dark mixturewas cooled to 35° C., and diluted slowly with cold water (150 kg). Themixture was filtered on an agitated Neutsche type filter, and thesulfonated beads were washed with water. Aqueous calcium acetatesolution (180 kg, 10% wt) was added, the mixture was agitated for 2hours, then filtered. Aqueous calcium acetate solution (180 kg, 10% wt)was added, the mixture was agitated for 2 hours, then filtered. Thebeads were washed with water. The filter cake was washed with acetoneand then dried under vacuum to give 25 kg of Example 32 as a light brownpowder. Particle Size: d(0.1)=19 μm; d(0.5)=35 μm; d(0.9)=54 μm. Ca-salt9.5 wt % (dry basis, by titration); K+ exchange capacity 1.5 mEq/g (perBP, dry basis); residual styrene <1 ppm; swelling ratio 5.6 (as is).

Example 33 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.8% Divinylbenzene (DVB)

Example 33 was prepared on 10 kg scale using methods analogous to thosedescribed for Example 32 with the following modifications:polymerization initiator was tert-butyl-peroxy-ethyl-hexanoate; aparticle size control (Dv0.5) of 50 microns was achieved via a jettingprocess (See e.g., Dow Chemical, U.S. Pat. No. 4,444,961). Aftersulfonation and calcium exchange; drying of the Ca-PSS was achieved viaa fluidized bed dryer. Particle Size (dry): d(0.1)=38; d(0.5)=51;d(0.9)=62. Ca-salt 9.7 wt % (by titration); K+ exchange capacity 1.5mEq/g (per BP).

Example 34 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with2.5% Divinylbenzene (DVB)

Example 34 was prepared on 500 g scale using methods analogous to thosedescribed for Example 33, and incorporating 2.5% divinylbenzene.Particle Size: d(0.1)=54 μm; d(0.5)=75 μm; d(0.9)=104 μm. K+ exchangecapacity 1.7 mEq/g (per BP); swelling ratio 3.7.

Example 35 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.5% Divinylbenzene (DVB)

Example 35 was prepared on 500 g scale using methods analogous to thosedescribed for Example 33, and incorporating 1.5% divinylbenzene.Particle Size: d(0.1)=54 μm; d(0.5)=78 μm; d(0.9)=114 μm. K+ exchangecapacity 1.4 mEq/g (per BP); swelling ratio 4.5.

Example 36 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.6% Divinylbenzene (DVB)

Example 36 was prepared on 500 g scale using methods analogous to thosedescribed for Example 33, and incorporating 1.6% divinylbenzene.Particle Size: d(0.1)=53 μm; d(0.5)=75 μm; d(0.9)=106 μm. K+ exchangecapacity 1.5 mEq/g (per BP); swelling ratio 4.5.

Example 37 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.7% Divinylbenzene (DVB)

Example 37 was prepared on 500 g scale using methods analogous to thosedescribed for Example 33, and incorporating 1.7% divinylbenzene.Particle Size: d(0.1)=53 μm; d(0.5)=74 μm; d(0.9)=105 μm. K+ exchangecapacity 1.5 mEq/g (per BP); swelling ratio 4.3.

Example 38 Preparation of Calcium Polystyrene Sulfonate (Ca-PSS) with1.8% Divinylbenzene (DVB)

Example 38 was prepared on 500 g scale using methods analogous to thosedescribed for Example 33, and incorporating 1.8% divinylbenzene.Particle Size: d(0.1)=51 μm; d(0.5)=77 μm; d(0.9)=114 μm. K+ exchangecapacity 1.5 mEq/g (per BP); swelling ratio 4.1.

Example 39 Calcium Polystyrene Sulfonate (Ca-PSS) with 1.8%Divinylbenzene (DVB)

Example 39 was prepared on 5.6 kg scale using methods analogous to thosedescribed for Example 29. Particle Size: d(0.1)=30 μm; d(0.5)=56 μm;d(0.9)=91 μm. K+ exchange capacity 1.4 mEq/g (per BP); swelling ratio5.1.

Example 40 Powder for Oral Suspension (POS), “Strawberry Smoothie”Flavor and Consistency, Sodium Free

Without a suspending agent, some Examples of the instant disclosuresettle out from water in a few minutes, highlighting the need for aviscosifying system. Hydrocolloids retard particle sedimentation byincreasing viscosity; however, at too high a viscosity, the formulationbecomes un-drinkable. To determine a maximum viscosity for a drinkableliquid, the viscosity of commercial liquid products were measured (Table6, below). Data were generated using a Brookfield EV-I viscometer usinga small sample size adapter with spindle 18, starting at 60 RPM anddecreasing speed as necessary to obtain an in-range reading. A targetviscosity of less than 400 cps was selected for a drinkable product,similar to a fruit-based blended smoothie.

TABLE 6 Viscosity of commercial liquid products Product Viscosity (cps)*Product Viscosity (cps)* Hershey's Chocolate Syrup 7528 Vermont MaidSyrup 635 Odwalla Strawberry Banana Smoothie 302 Pepto Bismol 195Syrpalta (Oral Dosing Vehicle) 86 Heavy Cream 18 Light Cream 7 *Note: itis understood to one skilled in the art that viscosity measurement is acomplicated field of science, and a single number may be anoversimplification of the system.

Additional criteria included a formulation that could readily disperse˜5 g of polymer in less than 35 mL water, and creation of a stablesuspension for the anticipated duration of consumption (approximately 5minutes). Last, it was desired to eliminate sodium from the formulationsince excess consumption of this electrolyte is contraindicated inkidney failure patients. In addition, a pH of ˜3-3.5 was chosen to becompatible with the stability and flavor properties of a fruit-themedformulation. The composition in Table 7, prepared from Example 39,achieves the above design considerations, and when added to ˜28-30 mL ofwater readily wets and suspends after brief and gentle mixing (inverting4-5 times in a closed container).

TABLE 7 Composition of Example 40 “strawberry smoothie”powder-for-oral-suspension Ingredient g/30 mL Suspension Calcium citratetetrahydrate 0.049 Citric acid, anhydrous 0.150 Sucralose 0.030Michaelock N&A Strawberry Flavor #2342 0.075 Methylcellulose A4C 0.150FD&C Red 3 (0.1% solution) 0.430 Titanium Dioxide 0.060 Example 39 5.00Water Qs to 30 mL (Resulting pH: 3.41

Example 41 Ready-To-Use (RTU) “Strawberry Smoothie” Drinkable Suspension

Example 41, a ready-to-use variant of Example 40, was prepared fromExample 39 by including a preservative system in the reconstitutedformulation, replacing anhydrous citric acid with benzoic acid (0.030g). This formulation is also sodium-free.

Example 42 Read-To-Use (RTU) Spoonable Formulation, Chocolate Flavored,Sodium Free

Higher viscosity formulations were found to attenuate the sensation ofgrittiness and improve the mouth feel characteristics of some Examplesdisclosed herein (see Biological Example 14). Example 42 is a“spoonable” yoghurt/gel based formulation that was developed with achocolate “indulgent” flavor theme (Table 8). This formulation alsoavoids sodium-containing excipients and has a near neutral pH (5.0),consistent with the flavor and stability requirements of the flavoringagent.

TABLE 8 Composition of Example 42, a “spoonable” chocolate-themedformulation Ingredient g/30 mL Suspension Calcium citrate tetrahydrate0.003 Citric acid, anhydrous 0.004 Sucralose 0.030 Xanthan gum 0.165Natural Chocolate Flavor #37620 0.120 Sorbic acid 0.015 Example 39 5.00Water 25 g (Resulting pH: 5.0

Example 43 Ready-To-Use (RTU) “Spoonable” Formulation, StrawberryFlavored, Sodium Free

Example 43 was prepared applying the principles described in Examples40-42 and Biological Example 14 to afford a fruit-themed, lower pHspoonable formulation (Table 9).

TABLE 9 Composition of Example 43, a “spoonable,” strawberry flavoredsodium free formulation Ingredient g/30 mL Suspension Calcium citratetetrahydrate 0.042 Citric acid, anhydrous 0.130 Sucralose 0.030 Xanthangum 0.135 Michaelock N&A strawberry flavor #2342 0.075 FD&C Red 3 (0.1%solution) 0.430 Titanium dioxide 0.060 Benzoic acid 0.025 Example 395.00 Water 25 g (Resulting pH: 3.3)

Example 44 Chewable Tablet Formulation, Citrus Flavored

A chewable tablet was designed by first determining an appropriatetablet hardness for a chewable dosage form: the tablets must be hardenough to hold together through processing and shipping, while stillmaintaining a chewable texture. Accordingly, the hardness of severalcommercially available chewable OTC products were measured (Table 10),after which a tablet hardness target of approximately 9-15 kp was set.

TABLE 10 Hardness of OTC chewable tablets Product Hardness (kp) TumsKids Antacid 7.4 Tums Smoothies 10.4 Spectravite Senior Chewable 11.9Tums Regular 12.4 Centrum Children's Chewable Vitamins 12.9 CVSChildren's Complete Chewable Vitamins 15.7 Flintstones Chewable Vitaminswith Iron 16.4

Apart from the active ingredient, a chewable tablet is composedprimarily (but not exclusively) of a tablet binder, hence multipletablet binders were explored in pilot tableting exercises. Theseincluded direct compression Lactose (Supertab 11SD-DSM), directcompression Mannitol (Pearlitol 100SD-Roquette), sucrose(Di-Pac-Domino), -sodium starch glycolate All-in-One (ProSolv EasytabSP-JRS) and a mannitol based All-in-One (ProSolv ODT G2-JRS). Drug loadwas explored with the goal of achieving a high percentage. Example 39was subjected to iterative screening in a number of the binder systemslisted above, and an approximately 30% loading was achieved in achewable tablet format. Tablets were created based on a 3 g gross tabletweight, with 900 mg Example 39 per tablet. Blends were loaded into a 25mm diameter tablet die and a Carver hydraulic hand press (Model 3912)was used to compress the blends to a maximum force of 15,000 lbs toafford tablets.

ProSolv Easytab SP had an extremely chalky mouth feel and was droppedfrom consideration, whereas both ProSolv ODT G2 and Pearlitol 100SD hadsimilar, smooth mouth feels and were advanced. Active ingredient loadingwas re-explored, and while a 41.66% drug load could not affordsufficiently hard tablets, a load of 33.3% was acceptable. Next, thesweet/sour properties of the tablets were determined. As sucralose andcitric acid had proven to be an effective pairing in the suspensionformulations, varying levels of these were evaluated in both bindersystems (Pearlitol 100SD w/ additives and ProSolv ODT G2). A finalsucralose level of 0.15% and citric acid of 1.5% provided the desiredsweet/sour balance. Finally, flavor candidates were screened in bothleading base binder systems, and included fruit flavored themes such ascitrus, orange, mixed berry, strawberry and punch. These wereincorporated into the mimetic (excipient) base starting at 0.25%, andadjusting up or down as appropriate. When the final mimetic (excipient)flavor systems (Pearlitol 100 SD with additives and ProSolv) werecompared side-by-side, it was apparent that the Pearlitol(mannitol-based) system had a better mouth feel overall, and wasselected as a preferred system. This formulation, Example 44, is shownbelow in Table 11.

TABLE 11 Composition of Example 44, a chewable tablet formulationMannitol based formulation Ingredient g/100 g Example 39 33.33 ColloidalSilicon Dioxide, NF-M-5P 0.85 Sucralose, NF 0.15 Magnesium Stearate, NF1.35 Croscarmellose Sodium, NF Ac-DI-Sol SD-711 NF 2.80 Avicel CE-155.30 Citric Acid, Anhydrous 1.50 Natural Orange Flavor #SC356177 0.45Mannitol, USP Pearlitol 100 SD 54.27

Example 45 Ready-To-Use (RTU) “Smoothie” Drinkable Suspension, Orangeand Vanilla Flavors

Example 37 was formulated into both an orange- and vanilla-flavoredready-to-use drinkable “smoothie” using the procedures and conceptsdescribed in Example 40 and Example 41. Both formulations aresodium-free.

TABLE 12 Compositions of Example 45, drinkable “smoothie” in both orangeand vanilla flavor Orange Vanilla formulation formulation (g/30 mL (g/30mL Ingredient suspension) suspension) Calcium Citrate Tetrahydrate 0.1490.066 Benzoic Acid 0.030 — Sorbic Acid — 0.015 Citric Acid Anhydrous0.150 0.004 Sucralose 0.030 0.030 Natural Orange WONF FV7466 0.150 —SuperVan Art Vanilla VM36 — 0.150 Methylcellulose A4C 0.165 0.165Titanium Dioxide — 0.120 Example 37 5.624 5.624 Water 25.72  25.68 

Example 46 Powder for Oral Suspension (POS), “Smoothie” Consistency,Orange- and Vanilla-Flavored, Sodium Free

Example 37 was formulated into both an orange- and vanilla-flavoredpowder-for-oral-suspension using the procedures and concepts describedin Example 40. Both formulations are sodium-free, and reconstitute to adrinkable suspension with the consistency of a fruit-based “smoothie”upon addition to one ounce of water and brief agitation.

TABLE 13 Compositions of Example 46, powders for oral suspension in bothorange and vanilla flavor Orange Vanilla formulation formulation (g/30mL (g/30 mL Ingredient suspension) suspension) Calcium CitrateTetrahydrate 0.149 0.066 Citric Acid Anhydrous 0.150 0.013 Sucralose0.030 0.030 Artificial orange flavored powder FV653 0.150 — Vanillinpowder — 0.060 Methylcellulose A4C 0.165 0.165 Titanium Dioxide — 0.120Example 37 (includes 11.1% water (KF)) 5.624 5.624

Example 47 “Spoonable” Formulation, Orange- and Vanilla-Flavored, SodiumFree

Example 37 was formulated into ready-to-use “spoonable” orange- andvanilla-flavored formulations using the procedures and conceptsdescribed in Example 42 and Example 43. Both formulations aresodium-free, and their composition is illustrated in Table 14.

TABLE 14 Compositions of Example 47, RTU orange- and vanilla- flavored“spoonable” suspensions Orange Vanilla formulation formulation (g/30 mL(g/30 mL Ingredient suspension) suspension) Calcium Citrate Tetrahydrate0.149 0.066 Benzoic Acid 0.030 — Sorbic Acid — 0.015 Citric AcidAnhydrous 0.150 0.004 Sucralose 0.030 0.030 Natural Orange WONF FV74660.150 — SuperVan Art Vanilla VM36 — 0.150 Xanthan Gum CP 0.210 0.180Titanium Dioxide — 0.120 Example 37 (includes 11.1% water (KF)) 5.6245.624 Water 25.0   25.0  

Biological Example 1 Preparation of Mice for In Vivo Animal Studies

Study Preparation:

Male CD-1 mice ˜25-35 grams (Charles River) were used for these studies.Upon arrival animals were allowed to acclimate in standard cages, onstandard chow before study initiation. The day of diet acclimationinitiation, body weights were obtained and mice were placed in metaboliccages. The animals were fed ad libitum during the study. Mice wereprovided normal powdered chow or study compound mixed in powdered chowat the designated percentage for a period of 48 hours (to ensure thestudy diet has passed the length of the GI and animals achieve “steadystate”). Food and water measurements were recorded upon placement ofanimals in metabolic cages, and every 24 hours until study completion.After 48 hours of acclimation, the 24 hour collection period began.Clean collection tubes were placed on the cage. Mice were provided theirdesignated study diet during the collection period. Urine and feces werecollected at the end of this 24 hour period. Food and water was weighedagain to determine the amount consumed over the study period.

Sample Processing and Analysis:

Urine and feces were collected directly into pre-weighed tubes placed onthe metabolic racks. At the collection time the urine tubes were cappedand the urine was weighed. The urine was then pipetted into a pair of 96well-plates with 0.2 ml of each urine sample added to each plate. Oneplate was acidified (20 μl of 6 N HCl per sample). Plates were storedfrozen until analysis. The feces were removed from the metabolic cages,the jars were capped, wet weights were recorded, and then the sampleswere frozen for ˜3-4 hours. The feces were then dried on a lyophilizerfor at least 3 days before a dry weight was taken and fecal fluidcontent was calculated. Feces and urine were analyzed by microwaveplasma-atomic emission spectroscopy (MP-AES) or ion chromatography (IC)for ion content.

Biological Example 2 Preparation of Rats for In Vivo Animal Studies

Study Preparation:

Male Sprague Dawley (Charles River) rats (˜200-250 gm) were used forthese studies. Upon arrival animals were allowed to acclimate instandard cages, on standard chow, for at least 2 days prior to studyinitiation. The day prior to being placed in metabolic cages, bodyweights were obtained and rats were provided normal powdered chow orstudy compound in powder chow, via a J-Feeder, beginning at ˜1:00 pm (toensure the study diet has passed the length of the GI). The day of thestudy, rats were transferred to metabolic cages at ˜3:30 pm, where theywere provided their designated study diet for 16 hours. Tare weights offood and water were obtained prior to animals being placed in the cages.Urine and feces were collected ˜16 hours later. Food and water wasweighed again to determine the amount consumed over the study period.

Chow Formulation:

Chow meal (Standard rodent chow, 2018C) was weighed out into a mixingbowl and placed on a stand mixer (KitchenAid). PSS was weighed out andadded to the chow to achieve the desired final concentration (2-8%polymer in chow by weight). The mixer was set to stir on low for atleast 10 minutes to evenly distribute the polymer in the chow. The chowwas then transferred to a labeled zip-lock storage bag.

Sample Processing and Analysis:

Urine was collected directly into pre-weighed 50 ml conical tubes placedinside the urine collectors on the metabolic racks. At the collectiontime the urine tubes were capped and the urine was weighed. The urinewas then pipetted into a pair of 96-well plates with 0.5 ml of eachurine sample added to each plate. One plate was acidified (50 μl of 6 NHCl per sample). Both plates were submitted on the same day forbioanalytical analysis (or were placed in a −20 freezer). The feces weretransferred from the metabolic collectors to pre-weighed capped jars,wet weights were recorded, and then the samples were frozen for ˜3-4hours. The feces were dried on a lyophilizer for at least 3 days beforea dry weight was taken and fecal fluid content calculated. The feceswere then placed on a homogenizer and ground to a fine powder. For eachsample, two aliquots were weighed out. 500 mg was weighed into a 50 mlconical tube, and 50 mg into an eppindorf tube. Feces and urine wereanalyzed by MP-AES or IC for ion content.

Biological Example 3 Effects on Fecal Potassium Levels in Rats UponDosing with Ca-PSS

Using the methods described in Biological Example 2, rats were dosedCa-PSS blended into chow at 4% or 8% wt/wt. These polymers had differinglevels of crosslinking (2%, 4% and 8% DVB crosslinking). In thisexperiment, all rats dosed with Ca-PSS blended into the diet at 8% wt/wthad significant increases in K excretion. The highest fecal K was seenin the group that was fed a 2% DVB crosslinked polymer, when saidpolymer was present at 8% wt/wt in chow. This increase was significantlyhigher than that observed for the other polymers that were similarlydosed as 8% wt/wt blends in chow (FIG. 2).

Biological Example 4 Effects on Potassium Excretion in Mice Upon Dosingwith Examples 4, 5, 6, Ca-PSS and BP

Using the methods described in Biological Example 1, mice were doseCa-PSS (i.e., polymers of Formula (I) or a pharmaceutically acceptablesalt thereof) blended into chow (Standard 2018 chow) at 8% wt/wt. Thepolymers had differing levels of crosslinking: 2% DVB, (Example 4); 4%DVB, (Example 5); 8% DVB (Example 6); and Ca-PSS, BP (Ca-PSS, BP with 8%DVB crosslinking) was used as a control. All mice dosed with Ca-PSSblended in the diet at 8% wt/wt had significant increases in Kexcretion. The highest level of K secretion was seen with the 2% DVBmaterial (Example 4, FIG. 3).

Biological Example 5 Effects on Potassium Excretion in Mice Upon Dosingwith Examples 4, 6, 9 and 10

Using the methods in Biological Example 1, mice were dosed Ca-PSS (i.e.,polymers of Formula (I) or a pharmaceutically acceptable salt thereof)blended into chow at 8% wt/wt. The test articles included the following:Vehicle (2018 chow); 200-400 mesh Ca-PSS with 2% DVB crosslinking(Example 4); 200-400 mesh Ca-PSS with 8% DVB crosslinking (Example 6),Ca-PSS polymer with 1.6% DVB cross-linking (Example 9), and Ca-PSSmaterial with 1.8% DVB cross-linking (Example 10). All mice dosed with8% wt/wt Ca-PSS in their diet had significant increases in K excretion.The highest levels of K secretion were seen with polymers possessing DVBlevels of 2% or less (FIG. 4). The level of K in the feces wassignificantly higher with 1.6%, 1.8% and 2% DVB (Examples 9, 10, and 4)compared to vehicle or 8% DVB (Example 6).

Biological Example 6 Effects on Fecal Potassium Levels in Mice UponDosing with Example 10, Na-PSS, USP, CA-PSS, and/or BP

Using the methods in Biological Example 1, mice were dosed Na-PSS, USP,Ca-PSS, BP and Example 10 blended into chow at 8% wt/wt. There was asignificant increase in fecal potassium in animals consuming eitherCa-PSS, BP or Example 10, with the highest fecal potassium seen inExample 10 (FIG. 5).

Biological Example 7 Effects on Fecal and Urinary Phosphate Levels inMice Upon Dosing with Example 10

Using the methods in Biological Example 1, mice were dosed with Na-PSS,USP and Example 10, blended into chow at 4% and 8% wt/wt. There was asignificant increase in fecal potassium in animals consuming eitherNa-PSS, USP or Example 10 when present at 8% w/w in chow, but onlyExample 10 showed a significant increase in fecal potassium at 4% wt/wtin chow. In addition there was significantly more K in the feces of micefed Example 10 versus Na-PSS, USP when these test articles were presentat 8% wt/wt in chow (FIG. 6). In addition, the group treated withExample 10 blended into chow at 8% wt/wt had higher levels of fecalphosphate compared to those mice identically dosed with Na-PSS, andlower levels of urinary phosphate compared to groups treated with bothNa-PSS or vehicle (FIG. 13).

Biological Example 8 Effects on Fecal Potassium Levels in Mice UponDosing with Example 10

Using the methods in Biological Example 1, mice were fed increasingamounts of Example 10 blended in chow a 2, 4, 6 and 8% wt/wt. Thecontrol group was fed standard rodent chow (Harlan Teklad 2018). Therewas a dose dependent increase in fecal potassium content with theaddition of Example 10 to the chow, with the highest fecal potassiumseen in the 8% wt/wt group (FIG. 7).

Biological Example 9 Effects on Fecal Potassium Levels in Mice UponDosing with Examples 10, 13, and 18

Using the methods in Biological Example 1, mice were dosed Ca-PSSblended into chow at 8% wt %1. The test articles included Example 10,Example 13 and Example 18; Example 6 served as a control. The level ofK⁺ in the feces was significantly higher for Examples 32, 35, and 41compared to Example 6. (FIG. 8).

Biological Example 10 Effects on Fecal Potassium Levels in Mice UponDosing with Examples 20 and 21

Using the methods in Biological Example 1, mice were dosed Ca-PSSblended into chow at 8% wt/wt. The test articles included Ca-PSS, BP asa control as well as Example 20 and Example 21, all of which wereblended into chow at 8% wt/wt (FIG. 9). The highest level of fecalpotassium was seen with Example 21.

Biological Example 11 Effects on Potassium Output in Mice Upon Dosingwith Examples 30 and 31

Using the methods in Biological Example 1, mice were dosed with resinsblended into chow at 8% wt/wt. The test article groups included Na-PSS,USP (US Pharmacopeia grade; Purolite, Inc.), Ca-PSS, BP (BritishPharmacopeia grade; Purolite, Inc.), Example 30, and Example 31. Groupsdosed with Na-PSS, USP and Example 30 had significantly lower fecal ionoutput, and had a mean K+ output of ˜8 mg/24 h. Ca-PSS, BP showed a meanK+ output of 15 mg/24 h. Example 31 had the highest K+ output in thisexample at 23 mg/24 h. Examples 30 and 31 were prepared from the samebatch of sulfonated resin, and differ only in salt form. (FIG. 14

Biological Example 12 Effects on Fecal Potassium and Phosphorus Levelsand Urinary Sodium and Potassium Levels in Mice Upon Dosing withExamples 32 and 33

Using the methods in Biological Example 1, mice were dosed with resinsblended into chow at 8% wt/wt. The test article groups included vehicle(normal chow without any drug), Na-PSS, USP, Example 32 and Example 33.Compared to Na-PSS, USP, both Example 32 and Example 33 resulted in 1)significantly higher amounts of fecal potassium, 2) significantly higheramounts of fecal phosphorus, and 3) significantly lower amounts of urinesodium and potassium. (FIG. 15 and FIG. 16)

Biological Example 13 Effects on Fecal Output in Mice Upon Dosing withExamples 34, 36, 37 and 37

Using the methods in Biological Example 1, mice were dosed with resinsblended into chow at 8% wt/wt. The test article groups included Na-PSS,USP, Example 34, Example 36, Example 37 and Example 38. Fecal outputs ofpotassium are significantly elevated for all Examples relative toNa-PSS, USP, while Examples 36, 37, and 38 cause higher fecal potassiumthan Example 34. (FIG. 13)

Biological Example 14 A Phase I Randomized Study to Evaluate the OverallConsumer Acceptability of Taste and Mouth Feel of Example 29 andFormulations Thereof in Healthy Subjects

The primary objective of the study was to evaluate the overallacceptability, as well as the acceptability of specific attributes, oftaste and mouth feel of different oral formulations of Example 29 incomparison to a reference formulation (Resonium A; sodium polystyrenesulfonate [Na PSS], Sanofi-Aventis). This was a single center,randomized, crossover study to evaluate the taste of different oralformulations of Example 29 in healthy subjects. Visit 1 was open-labeland Visit 2 was single-blind for Regimens E to I and open-label forRegimen J which was tested last. Formulation regimens are shown in Table15, and include a systematic exploration of viscosity (by varying theamount of xanthan gum) and flavor (vanilla, citrus and mint).

Subjects were screened for inclusion in the study up to 28 days beforedosing. Eligible subjects were admitted to the unit at approximately21:00 on the evening before administration of the first regimen (Day −1)and were either discharged following the last taste test or remained onsite until approximately 24 hours post-initial tasting, depending onwhichever was most convenient for the subject.

TABLE 15 Formulations for Biological Example 14 Regimen DescriptionFormulation A Resonium A reconstituted in water Resonium A containssaccharine per patient instructions (3 mL-4 mL (sweetener) and vanillin(flavouring agent) of water/g) B Example 29 reconstituted (in water)Identical excipients and equivalent with saccharine and vanillinformulation as Regimen A C Example 29 suspension formulation Water-basedsuspension containing in vanilla flavour Example 29 (16.5%), vanillin(0.17%), methylparaben (0.18%) propylparaben (0.02%), sucralose powder(0.02%) and xanthan gum (0.67%) D Example 29 jelly formulations in Sameas Regimen C except xanthan gum vanilla flavour was present at 1.00% EExample 29 jelly formulation in Identical to Regimen D vanilla flavour FExample 29 jelly formulation in Same as Regiment D except vanillin wascitrus flavour replaced with N&A Orange Flavor Powder, Flavor Producersitem No. M680957M G Example 29 jelly formulation in Equivalent toRegimen D except vanillin wintergreen garden mint flavour was replacedwith Wintergreen Garden Mint (FL Emul. N&A WS), Sensient item No.SN2000016303 H Example 29 suspension low viscosity Same as Regimen Fexcept xanthan gum formulation in citrus yoghurt flavour was present at0.37% I Example 29 intermediate viscosity Same as Regimen F exceptxanthan gum formulation in citrus flavour was present at 0.67% J Example29 reconstituted Same as Regimen B except vanillin was formulation incitrus flavour replaced with N&A Orange Flavor Powder, Flavor Producersitem No. M680957M

Taste testing occurred over two visits. During Visit 1, each subjectreceived 1 g each of regimen A, B, C and D in a randomized order using aLatin square design. Each regimen was administered as 4 to 6 mL offormulation, and each subject tasted all 4 regimens. During Visit 2,each subject received approximately 5 mL each of regimen E, F, G, H, Iand J. All formulations were administered orally. Taste was assessedusing a questionnaire designed by Sensory Research Ltd (Cork, Ireland).The questionnaire asked subjects to rate the acceptability of severalparameters (including smell, sweetness, flavor, mouth feel/texture andgrittiness), as well as overall acceptability, on a 9 point scale (from1—dislike everything to 9—like extremely).

No formal statistical testing was performed on screening or baselinedata. The data from the results of the taste test were summarized (mean,median, SD, CV (%), minimum, maximum and N) by regimen for Visit 1 andVisit 2 separately. The number and percentage of subjects assigned toeach grade of the acceptability categories on the taste questionnairewere also summarized by regimen for Visit 1 and Visit 2 separately. Theformulation with the highest median score on overall acceptability wasconsidered the formulation with the most acceptable taste profile andmouth feel.

Visit 1.

Regimen A (Resonium A) was consistently the poorest performingformulation throughout the taste assessment illustrating that Example29, and formulations of Example 29, provide superior acceptability toResonium A (Table 16). For Visit 1, although Regimen D (“jellyformulation” flavored by vanillin) had the highest overall median score,Regimen C (suspension formulation flavored by vanillin) produced similarresults (Table 16). It was concluded that Regimen D would be reassessedat Visit 2, including favor variants.

TABLE 16 Taste Testing Results from Visit 1 Median score (mean)Mouthfeel/ Regimen Smell Sweetness Flavor texture Grittiness OverallRegimen A 5.0 (5.5) 5.0 (5.9) 5.0 (5.4) 3.0 (3.4) 3.0 (2.8) 4.0 (4.3)Regimen B 5.5 (6.1) 6.0 (6.1) 5.5 (5.6) 4.5 (4.9) 3.5 (4.3) 5.0 (5.1)Regimen C 7.0 (7.0) 7.0 (7.0) 7.0 (6.6) 6.0 (5.4) 5.5 (5.9) 6.0 (6.2)Regimen D 7.5 (7.2) 7.0 (6.5) 7.0 (6.1) 6.0 (5.3) 6.0 (6.3) 7.0 (6.2)Highest scores per assessment are shown in bold

Visit 2.

Regimen E (jelly formulation in vanilla flavor, identical to Regimen D)had the joint highest median and highest mean scores for overall tasteassessment, as well as scoring highest in most of the other tasteassessments (Table 17). Regimen F afforded responses similar to RegimenE but scored higher for grittiness. Regimens E, F and G were all jellyformulations investigating different flavor options: vanilla, citrus andwintergreen garden mint, respectively. The vanilla and citrus scored thesame median score for flavor, with vanilla scoring more consistentlyacross subjects, suggesting this is the preferred flavor. Wintergreenmint had the lowest median scores for flavor. Regimens F, H, I and Jwere formulations of differing viscosity with the same citrus flavor.Regimen F (jelly formulation; 1% xanthan gum) had the highest medianscore compared to the other citrus formulations, confirming the resultsfrom the Visit 1 assessments (i.e. a “jelly” formulation is thepreferred viscosity) (Table 17).

Example 29 consistently outperformed Resonium A in all aspects of thetaste assessments. The jelly formulation was the preferred viscosity andvanilla (flavored by vanillin) and citrus were comparable for flavor;however, vanilla (flavored by vanillin) scored more consistently thancitrus, suggesting it was the preferred flavor.

TABLE 17 Taste Testing Results from Visit 2 Median score (mean)Mouthfeel/ Regimen Smell Sweetness Flavor texture Grittiness OverallRegimen E 7.0 (6.9) 7.0 (7.0) 7.0 (6.9) 7.0 (6.5) 6.0 (6.2) 7.0 (6.8)Regimen F 6.5 (6.4) 7.0 (6.8) 7.0 (6.5) 6.5 (6.4) 6.5 (6.3) 7.0 (6.4)Regimen G 5.0 (5.5) 6.0 (5.5) 6.0 (5.4) 5.0 (5.3) 5.5 (5.7) 5.0 (5.3)Regimen H 6.0 (5.7) 6.5 (6.1) 6.0 (5.9) 6.0 (5.8) 5.5 (5.7) 6.0 (5.7)Regimen I 6.0 (5.9 6.0 (6.2) 6.0 (6.1) 6.0 (5.8) 5.0 (5.7) 6.0 (6.0)Regimen J 5.0 (4.9) 5.5 (5.2) 4.5 (4.6) 4.0 (4.1) 4.0 (4.0) 4.0 (4.1)Highest scores per assessment are shown in bold and lowest scores initalics

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

What is claimed is:
 1. A calcium salt of a crosslinked potassium bindingpolymer having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each R₁ isindependently selected from the group consisting of H, substituted orunsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₆-C₁₈)aryl,—S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; eachR₂ is independently selected from the group consisting of H, substitutedor unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH; each R₃ is independently selected from the group consistingof H, halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH; each X is either absent or independentlyselected from the group consisting of substituted or unsubstituted(C₁-C₆)alkyl and substituted or unsubstituted (C₆-C₁₈)aryl, each Y isindependently selected from the group consisting of substituted orunsubstituted (C₁-C₆)alkyl and substituted or unsubstituted(C₆-C₁₈)aryl; and the mole ratio of m to n is from about 120:1 to about40:1; and wherein the crosslinked potassium binding polymer ischaracterized by a crosslinking of less than 5%.
 2. The crosslinkedpotassium binding polymer of claim 1, wherein the ratio of m to n isfrom about 70:1 to about 50:1.
 3. The crosslinked potassium bindingpolymer of claim 1 or 2, wherein the ratio of m to n is from about 70:1to about 60:1.
 4. The crosslinked potassium binding polymer of any oneof claims 1 to 3, wherein the ratio of m to n is about 68:1.
 5. Thecrosslinked potassium binding polymer of any one of claims 1 to 4,wherein Y is phenyl.
 6. The crosslinked potassium binding polymer of anyone of claims 1 to 5, wherein X is absent or phenyl.
 7. The crosslinkedpotassium binding polymer of any one of claims 1 to 6, wherein X isabsent and R₁ is H when XR₁ is attached to the carbon atom substitutedwith Y.
 8. The crosslinked potassium binding polymer of any one ofclaims 1 to 7, wherein R₃ is H.
 9. The crosslinked potassium bindingpolymer of any one of claims 1 to 6 and 8, wherein R₁ and R₂ are eachindependently H or —S(O)₂OH.
 10. The crosslinked potassium bindingpolymer of any one of claims 1 to 9, wherein the potassium bindingpolymer is characterized by a swelling ratio in water of between about 3grams of water per gram of polymer to about 8 grams of water per gram ofpolymer.
 11. The crosslinked potassium binding polymer of any one ofclaims 1 to 10, wherein the potassium binding polymer is characterizedby a swelling ratio in water of between about 3 grams of water per gramof polymer to about 4.5 grams of water per gram of polymer.
 12. Thecrosslinked potassium binding polymer of any one of claims 1 to 11,wherein the potassium binding polymer is characterized by a swellingratio in water of about 3.3 grams of water per gram of polymer.
 13. Thecrosslinked potassium binding polymer of any one of claims 1 to 11,wherein the potassium binding polymer is characterized by a swellingratio in water of about 4.3 grams of water per gram of polymer.
 14. Thecrosslinked potassium binding polymer of any one of claims 1 to 13,wherein the potassium binding polymer further comprises substantiallyspherical particles having a median diameter from about 5 μm to about130 μm.
 15. The crosslinked potassium binding polymer of claim 14,wherein the particles have an average particle size Dv(0.9) betweenabout 80 μm to about 130 μm.
 16. The crosslinked potassium bindingpolymer of claim 14 or 15, wherein the particles have an averageparticle size Dv(0.9) between about 90 μm to about 120 μm.
 17. Thecrosslinked potassium binding polymer of claim 14, wherein the particleshave an average particle size Dv(0.9) between about 40 μm to about 70μm.
 18. The crosslinked potassium binding polymer of claim 14 or 17,wherein the particles have an average particle size Dv(0.9) betweenabout 50 μm to about 60 μm.
 19. The crosslinked potassium bindingpolymer of any one of claims 14 to 18, wherein the particles have anaverage particle size Dv(0.5) between about 60 μm to about 90 μm. 20.The crosslinked potassium binding polymer of any one of claims 14 to 19,wherein the particles have an average particle size Dv(0.5) betweenabout 70 μm to about 80 μm.
 21. The crosslinked potassium bindingpolymer of any one of claims 14 to 18, wherein the particles have anaverage particle size Dv(0.5) between about 20 μm to about 50 μm. 22.The crosslinked potassium binding polymer of any one of claims 14 to 18and 21, wherein the particles have an average particle size Dv(0.5)between about 30 μm to about 40 μm.
 23. The crosslinked potassiumbinding polymer of any one of claims 14 to 22, wherein the particleshave an average particle size Dv(0.1) between about 20 μm to about 70μm.
 24. The crosslinked potassium binding polymer of any one of claims14 to 23, wherein the particles have an average particle size Dv(0.1)between about 30 μm to about 60 μm.
 25. The crosslinked potassiumbinding polymer of any one of claims 14 to 22, wherein the particleshave an average particle size Dv(0.1) between about 5 μm to about 30 μm.26. The crosslinked potassium binding polymer of any one of claims 14 to22 and 25, wherein the particles have an average particle size Dv(0.1)between about 6 μm to about 23 μm.
 27. The crosslinked potassium bindingpolymer of any one of claims 1 to 26, wherein ratio of Dv(0.9):Dv(0.5)is about two or less and the ratio of Dv(0.5):Dv(0.1) is about five orless.
 28. The crosslinked potassium binding polymer of any one of claims1 to 27, wherein the ratio of Dv(0.9):Dv(0.5) and the ratio ofDv(0.5):Dv(0.1) are each independently about two or less.
 29. Thecrosslinked potassium binding polymer of any one of claims 1 to 28,wherein the potassium binding polymer has a potassium exchange capacityfrom about 1 mEq to about 4 mEq per gram of potassium binding polymer.30. The crosslinked potassium binding polymer of any one of claims 1 to29, wherein the potassium binding polymer has a Mouth Feel score greaterthan 3.5.
 31. The crosslinked potassium binding polymer of any one ofclaims 1 to 30, wherein the potassium binding polymer has a Mouth Feelscore greater than 4.5.
 32. The crosslinked potassium binding polymer ofany one of claims 1 to 31, wherein the potassium binding polymer has aMouth Feel score greater than 5.0.
 33. The crosslinked potassium bindingpolymer of any one of claims 1 to 32, wherein the potassium bindingpolymer is characterized by a crosslinking of less than 3%.
 34. Thecrosslinked potassium binding polymer of any one of claims 1 to 33,wherein the potassium binding polymer is characterized by a crosslinkingof about 1.8%, wherein the term about means±20%.
 35. The crosslinkedpotassium binding polymer of any one of claims 1 to 33, wherein thepotassium binding polymer is characterized by a crosslinking of about1.8%, wherein the term about means±10%.
 36. The crosslinked potassiumbinding polymer of any one of claims 1 to 33, wherein the potassiumbinding polymer is characterized by a crosslinking of about 1.8%,wherein the term about means±5%.
 37. The crosslinked potassium bindingpolymer of any one of claims 1 to 33, wherein the potassium bindingpolymer is characterized by a crosslinking of 1.8%.
 38. A calcium saltof a crosslinked potassium binding polymer having the structure ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein: each R₁ isindependently selected from the group consisting of H, substituted orunsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₆-C₁₈)aryl,—S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; eachR₂ is independently selected from the group consisting of H, substitutedor unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH; each R₃ is independently selected from the group consistingof H, halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH; each X is either absent or independentlyselected from the group consisting of substituted or unsubstituted(C₁-C₆)alkyl and substituted or unsubstituted (C₆-C₁₈)aryl; each Y isindependently selected from the group consisting of substituted orunsubstituted (C₁-C₆)alkyl and substituted or unsubstituted(C₆-C₁₈)aryl; and the mole ratio of m to n is from about 120:1 to about40:1; and wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 5μm to about 130 μm and wherein the crosslinked potassium binding polymeris characterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.
 39. The crosslinked potassium binding polymer of claim 38,wherein the ratio of m to n is from about 70:1 to about 50:1.
 40. Thecrosslinked potassium binding polymer of claim 38 or 39, wherein theratio of m to n is from about 70:1 to about 60:1.
 41. The crosslinkedpotassium binding polymer of any one of claims 38 to 40, wherein theratio of m to n is about 68:1.
 42. The crosslinked potassium bindingpolymer of any one of claims 38 to 41, wherein Y is phenyl.
 43. Thecrosslinked potassium binding polymer of any one of claims 38 to 42,wherein X is absent or phenyl.
 44. The crosslinked potassium bindingpolymer of any one of claims 38 to 43, wherein X is absent and R₁ is Hwhen XR₁ is attached to the carbon atom substituted with Y.
 45. Thecrosslinked potassium binding polymer of any one of claims 38 to 44,wherein R₃ is H.
 46. The crosslinked potassium binding polymer of anyone of claims 38 to 43 and 45, wherein R₁ and R₂ are each independentlyH or —S(O)₂OH.
 47. The crosslinked potassium binding polymer of any oneof claims 38 to 46, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 8 grams of water per gram of polymer.48. The crosslinked potassium binding polymer of any one of claims 38 to47, wherein the potassium binding polymer is characterized by a swellingratio in water of between about 3 grams of water per gram of polymer toabout 4.5 grams of water per gram of polymer.
 49. The crosslinkedpotassium binding polymer of any one of claims 38 to 48, wherein thepotassium binding polymer is characterized by a swelling ratio in waterof about 4.3 grams of water per gram of polymer.
 50. The crosslinkedpotassium binding polymer of any one of claims 38 to 49, wherein theparticles have an average particle size Dv(0.9) between about 80 μm toabout 130 μm.
 51. The crosslinked potassium binding polymer of any oneof claims 38 to 50, wherein the particles have an average particle sizeDv(0.9) between about 90 μm to about 120 μm.
 52. The crosslinkedpotassium binding polymer of any one of claims 38 to 49, wherein theparticles have an average particle size Dv(0.9) between about 40 μm toabout 70 μm.
 53. The crosslinked potassium binding polymer of any one ofclaims 38 to 49 and 52, wherein the particles have an average particlesize Dv(0.9) between about 50 μm to about 60 μm.
 54. The crosslinkedpotassium binding polymer of any one of claims 38 to 53, wherein theparticles have an average particle size Dv(0.5) between about 60 μm toabout 90 μm.
 55. The crosslinked potassium binding polymer of any one ofclaims 38 to 54, wherein the particles have an average particle sizeDv(0.5) between about 70 μm to about 80 μm.
 56. The crosslinkedpotassium binding polymer of any one of claims 38 to 53, wherein theparticles have an average particle size Dv(0.5) between about 20 μm toabout 50 μm.
 57. The crosslinked potassium binding polymer of any one ofclaims 38 to 53 and 56, wherein the particles have an average particlesize Dv(0.5) between about 30 μm to about 40 μm.
 58. The crosslinkedpotassium binding polymer of any one of claims 38 to 57, wherein theparticles have an average particle size Dv(0.1) between about 20 μm toabout 70 μm.
 59. The crosslinked potassium binding polymer of any one ofclaims 38 to 58, wherein the particles have an average particle sizeDv(0.1) between about 30 μm to about 60 μm.
 60. The crosslinkedpotassium binding polymer of any one of claims 38 to 57, wherein theparticles have an average particle size Dv(0.1) between about 5 μm toabout 30 μm.
 61. The crosslinked potassium binding polymer of any one ofclaims 38 to 57 and 60, wherein the particles have an average particlesize Dv(0.1) between about 6 μm to about 23 μm.
 62. The crosslinkedpotassium binding polymer of any one of claims 38 to 61, wherein ratioof Dv(0.9):Dv(0.5) is about two or less and the ratio of Dv(0.5):Dv(0.1)is about five or less.
 63. The crosslinked potassium binding polymer ofany one of claims 38 to 62, wherein the ratio of Dv(0.9):Dv(0.5) and theratio of Dv(0.5):Dv(0.1) are each independently about two or less. 64.The crosslinked potassium binding polymer of any one of claims 38 to 63,wherein the potassium binding polymer has a potassium exchange capacityfrom about 1 mEq to about 4 mEq per gram of potassium binding polymer.65. The crosslinked potassium binding polymer of any one of claims 38 to64, wherein the potassium binding polymer has a Mouth Feel score greaterthan 3.5.
 66. The crosslinked potassium binding polymer of any one ofclaims 38 to 65, wherein the potassium binding polymer has a Mouth Feelscore greater than 4.5.
 67. The crosslinked potassium binding polymer ofany one of claims 38 to 66, wherein the potassium binding polymer has aMouth Feel score greater than 5.0.
 68. A calcium salt of a crosslinkedpotassium binding polymer having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each R₁ isindependently selected from the group consisting of H, substituted orunsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₆-C₁₈)aryl,—S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; eachR₂ is independently selected from the group consisting of H, substitutedor unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH; each R₃ is independently selected from the group consistingof H, halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH; each X is either absent or independentlyselected from the group consisting of substituted or unsubstituted(C₁-C₆)alkyl and substituted or unsubstituted (C₆-C₁₈)aryl; each Y isindependently selected from the group consisting of substituted orunsubstituted (C₁-C₆)alkyl and substituted or unsubstituted(C₆-C₁₈)aryl; and the mole ratio of m to n is from about 120:1 to about40:1; and wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 25μm to about 125 μm and wherein the crosslinked potassium binding polymeris characterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.
 69. The crosslinked potassium binding polymer of claim 68,wherein the ratio of m to n is from about 70:1 to about 50:1.
 70. Thecrosslinked potassium binding polymer of claim 68 or 69, wherein theratio of m to n is from about 70:1 to about 60:1.
 71. The crosslinkedpotassium binding polymer of any one of claims 68 to 70, wherein theratio of m to n is about 68:1.
 72. The crosslinked potassium bindingpolymer of any one of claims 68 to 71, wherein Y is phenyl.
 73. Thecrosslinked potassium binding polymer of any one of claims 68 to 72,wherein X is absent or phenyl.
 74. The crosslinked potassium bindingpolymer of any one of claims 68 to 73, wherein X is absent and R₁ is Hwhen XR₁ is attached to the carbon atom substituted with Y.
 75. Thecrosslinked potassium binding polymer of any one of claims 68 to 74,wherein R₃ is H.
 76. The crosslinked potassium binding polymer of anyone of claims 68 to 73 and 75, wherein R₁ and R₂ are each independentlyH or —S(O)₂OH.
 77. The crosslinked potassium binding polymer of any oneof claims 68 to 76, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 8 grams of water per gram of polymer.78. The crosslinked potassium binding polymer of any one of claims 68 to77, wherein the potassium binding polymer is characterized by a swellingratio in water of between about 3 grams of water per gram of polymer toabout 4.5 grams of water per gram of polymer.
 79. The crosslinkedpotassium binding polymer of any one of claims 68 to 78, wherein thepotassium binding polymer is characterized by a swelling ratio in waterof about 4.3 grams of water per gram of polymer.
 80. The crosslinkedpotassium binding polymer of any one of claims 68 to 79, wherein theparticles have an average particle size Dv(0.9) between about 80 μm toabout 130 μm.
 81. The crosslinked potassium binding polymer of any oneof claims 68 to 80, wherein the particles have an average particle sizeDv(0.9) between about 90 μm to about 120 μm.
 82. The crosslinkedpotassium binding polymer of any one of claims 68 to 81, wherein theparticles have an average particle size Dv(0.5) between about 60 μm toabout 90 μm.
 83. The crosslinked potassium binding polymer of any one ofclaims 68 to 82, wherein the particles have an average particle sizeDv(0.5) between about 70 μm to about 80 μm.
 84. The crosslinkedpotassium binding polymer of any one of claims 68 to 83, wherein theparticles have an average particle size Dv(0.1) between about 20 μm toabout 70 μm.
 85. The crosslinked potassium binding polymer of any one ofclaims 68 to 84, wherein the particles have an average particle sizeDv(0.1) between about 30 m to about 60 μm.
 86. The crosslinked potassiumbinding polymer of any one of claims 68 to 85, wherein ratio ofDv(0.9):Dv(0.5) is about two or less and the ratio of Dv(0.5):Dv(0.1) isabout five or less.
 87. The crosslinked potassium binding polymer of anyone of claims 68 to 86, wherein the ratio of Dv(0.9):Dv(0.5) and theratio of Dv(0.5):Dv(0.1) are each independently about two or less. 88.The crosslinked potassium binding polymer of any one of claims 68 to 87,wherein the potassium binding polymer has a potassium exchange capacityfrom about 1 mEq to about 4 mEq per gram of potassium binding polymer.89. The crosslinked potassium binding polymer of any one of claims 68 to88, wherein the potassium binding polymer has a Mouth Feel score greaterthan 3.5.
 90. The crosslinked potassium binding polymer of any one ofclaims 68 to 89, wherein the potassium binding polymer has a Mouth Feelscore greater than 4.5.
 91. The crosslinked potassium binding polymer ofany one of claims 68 to 90, wherein the potassium binding polymer has aMouth Feel score greater than 5.0.
 92. A calcium salt of a crosslinkedpotassium binding polymer having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each R₁ isindependently selected from the group consisting of H, substituted orunsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₆-C₁₈)aryl,—S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; eachR₂ is independently selected from the group consisting of H, substitutedor unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH; each R₃ is independently selected from the group consistingof H, halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH; each X is either absent or independentlyselected from the group consisting of substituted or unsubstituted(C₁-C₆)alkyl and substituted or unsubstituted (C₆-C₁₈)aryl; each Y isindependently selected from the group consisting of substituted orunsubstituted (C₁-C₆)alkyl and substituted or unsubstituted(C₆-C₁₈)aryl; and the mole ratio of m to n is from about 120:1 to about40:1; and wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 5μm to about 70 μm and wherein the crosslinked potassium binding polymeris characterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.
 93. The crosslinked potassium binding polymer of claim 92,wherein the ratio of m to n is from about 70:1 to about 50:1.
 94. Thecrosslinked potassium binding polymer of claim 92 or 93, wherein theratio of m to n is from about 70:1 to about 60:1.
 95. The crosslinkedpotassium binding polymer of any one of claims 92 to 94, wherein theratio of m to n is about 68:1.
 96. The crosslinked potassium bindingpolymer of any one of claims 92 to 95, wherein Y is phenyl.
 97. Thecrosslinked potassium binding polymer of any one of claims 92 to 96,wherein X is absent or phenyl.
 98. The crosslinked potassium bindingpolymer of any one of claims 92 to 97, wherein X is absent and R₁ is Hwhen XR₁ is attached to the carbon atom substituted with Y.
 99. Thecrosslinked potassium binding polymer of any one of claims 92 to 98,wherein R₃ is H.
 100. The crosslinked potassium binding polymer of anyone of claims 92 to 97 and 99, wherein R₁ and R₂ are each independentlyH or —S(O)₂OH.
 101. The crosslinked potassium binding polymer of any oneof claims 92 to 100, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 8 grams of water per gram of polymer.102. The crosslinked potassium binding polymer of any one of claims 92to 101, wherein the potassium binding polymer is characterized by aswelling ratio in water of between about 3 grams of water per gram ofpolymer to about 4.5 grams of water per gram of polymer.
 103. Thecrosslinked potassium binding polymer of any one of claims 92 to 102,wherein the potassium binding polymer is characterized by a swellingratio in water of about 4.3 grams of water per gram of polymer.
 104. Thecrosslinked potassium binding polymer of any one of claims 92 to 103,wherein the particles have an average particle size Dv(0.9) betweenabout 40 μm to about 70 μm.
 105. The crosslinked potassium bindingpolymer of any one of claims 92 to 104, wherein the particles have anaverage particle size Dv(0.9) between about 50 μm to about 60 μm. 106.The crosslinked potassium binding polymer of any one of claims 92 to105, wherein the particles have an average particle size Dv(0.5) betweenabout 20 μm to about 50 μm.
 107. The crosslinked potassium bindingpolymer of any one of claims 92 to 106, wherein the particles have anaverage particle size Dv(0.5) between about 30 μm to about 40 μm. 108.The crosslinked potassium binding polymer of any one of claims 92 to107, wherein the particles have an average particle size Dv(0.1) betweenabout 5 μm to about 25 μm.
 109. The crosslinked potassium bindingpolymer of any one of claims 92 to 108, wherein the particles have anaverage particle size Dv(0.1) between about 6 μm to about 23 μm. 110.The crosslinked potassium binding polymer of any one of claims 92 to109, wherein ratio of Dv(0.9):Dv(0.5) is about two or less and the ratioof Dv(0.5):Dv(0.1) is about five or less.
 111. The crosslinked potassiumbinding polymer of any one of claims 92 to 110, wherein the ratio ofDv(0.9):Dv(0.5) and the ratio of Dv(0.5):Dv(0.1) are each independentlyabout two or less.
 112. The crosslinked potassium binding polymer of anyone of claims 92 to 111, wherein the potassium binding polymer has apotassium exchange capacity from about 1 mEq to about 4 mEq per gram ofpotassium binding polymer.
 113. The crosslinked potassium bindingpolymer of any one of claims 92 to 112, wherein the potassium bindingpolymer has a Mouth Feel score greater than 3.5.
 114. The crosslinkedpotassium binding polymer of any one of claims 92 to 113, wherein thepotassium binding polymer has a Mouth Feel score greater than 4.5. 115.The crosslinked potassium binding polymer of any one of claims 92 to114, wherein the potassium binding polymer has a Mouth Feel scoregreater than 5.0.
 116. A calcium salt of a crosslinked potassium bindingpolymer having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each R₁ isindependently selected from the group consisting of H, substituted orunsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₆-C₁₈)aryl,—S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; eachR₂ is independently selected from the group consisting of H, substitutedor unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH; each R₃ is independently selected from the group consistingof H, halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH; each X is either absent or independentlyselected from the group consisting of substituted or unsubstituted(C₁-C₆)alkyl and substituted or unsubstituted (C₆-C₁₈)aryl; each Y isindependently selected from the group consisting of substituted orunsubstituted (C₁-C₆)alkyl and substituted or unsubstituted(C₆-C₁₈)aryl; and the mole ratio of m to n is from about 120:1 to about40:1; and wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 20μm to about 130 μm, wherein the potassium binding polymer has a MouthFeel score greater than 3.5, and wherein the crosslinked potassiumbinding polymer is characterized by a crosslinking of about 1.8%,wherein the term about means±10%.
 117. The crosslinked potassium bindingpolymer of claim 116, wherein the ratio of m to n is from about 70:1 toabout 50:1.
 118. The crosslinked potassium binding polymer of claim 116or 117, wherein the ratio of m to n is from about 70:1 to about 60:1.119. The crosslinked potassium binding polymer of any one of claims 116to 118, wherein the ratio of m to n is about 68:1.
 120. The crosslinkedpotassium binding polymer of any one of claims 116 to 119, wherein Y isphenyl.
 121. The crosslinked potassium binding polymer of any one ofclaims 116 to 120, wherein X is absent or phenyl.
 122. The crosslinkedpotassium binding polymer of any one of claims 116 to 121, wherein X isabsent and R₁ is H when XR₁ is attached to the carbon atom substitutedwith Y.
 123. The crosslinked potassium binding polymer of any one ofclaims 116 to 122, wherein R₃ is H.
 124. The crosslinked potassiumbinding polymer of any one of claims 116 to 121 and 123, wherein R₁ andR₂ are each independently H or —S(O)₂OH.
 125. The crosslinked potassiumbinding polymer of any one of claims 116 to 124, wherein the potassiumbinding polymer is characterized by a swelling ratio in water of betweenabout 3 grams of water per gram of polymer to about 8 grams of water pergram of polymer.
 126. The crosslinked potassium binding polymer of anyone of claims 116 to 125, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 4.5 grams of water per gram ofpolymer.
 127. The crosslinked potassium binding polymer of any one ofclaims 116 to 126, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of about 4.3 grams of waterper gram of polymer.
 128. The crosslinked potassium binding polymer ofany one of claims 116 to 127, wherein the particles have an averageparticle size Dv(0.9) between about 80 μm to about 130 μm.
 129. Thecrosslinked potassium binding polymer of any one of claims 116 to 128,wherein the particles have an average particle size Dv(0.9) betweenabout 90 μm to about 120 μm.
 130. The crosslinked potassium bindingpolymer of any one of claims 116 to 129, wherein the particles have anaverage particle size Dv(0.5) between about 60 μm to about 90 μm. 131.The crosslinked potassium binding polymer of any one of claims 116 to130, wherein the particles have an average particle size Dv(0.5) betweenabout 70 μm to about 80 μm.
 132. The crosslinked potassium bindingpolymer of any one of claims 116 to 131, wherein the particles have anaverage particle size Dv(0.1) between about 20 μm to about 70 μm. 133.The crosslinked potassium binding polymer of any one of claims 116 to132, wherein the particles have an average particle size Dv(0.1) betweenabout 30 μm to about 60 μm.
 134. The crosslinked potassium bindingpolymer of any one of claims 116 to 133, wherein ratio ofDv(0.9):Dv(0.5) is about two or less and the ratio of Dv(0.5):Dv(0.1) isabout five or less.
 135. The crosslinked potassium binding polymer ofany one of claims 116 to 134, wherein the ratio of Dv(0.9):Dv(0.5) andthe ratio of Dv(0.5):Dv(0.1) are each independently about two or less.136. The crosslinked potassium binding polymer of any one of claims 116to 135, wherein the potassium binding polymer has a potassium exchangecapacity from about 1 mEq to about 4 mEq per gram of potassium bindingpolymer.
 137. The crosslinked potassium binding polymer of any one ofclaims 116 to 136, wherein the potassium binding polymer has a MouthFeel score greater than 4.5.
 138. The crosslinked potassium bindingpolymer of any one of claims 116 to 137, wherein the potassium bindingpolymer has a Mouth Feel score greater than 5.0.
 139. A calcium salt ofa crosslinked potassium binding polymer having the structure of Formula(I):

or a pharmaceutically acceptable salt thereof, wherein: each R₁ isindependently selected from the group consisting of H, substituted orunsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₆-C₁₈)aryl,—S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; eachR₂ is independently selected from the group consisting of H, substitutedor unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted(C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and—NHS(O)₂OH; each R₃ is independently selected from the group consistingof H, halogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted orunsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH; each X is either absent or independentlyselected from the group consisting of substituted or unsubstituted(C₁-C₆)alkyl and substituted or unsubstituted (C₆-C₁₈)aryl; each Y isindependently selected from the group consisting of substituted orunsubstituted (C₁-C₆)alkyl and substituted or unsubstituted(C₆-C₁₈)aryl; and the mole ratio of m to n is from about 120:1 to about40:1; and wherein the crosslinked potassium binding polymer comprisessubstantially spherical particles having a median diameter from about 5μm to about 70 μm, wherein the potassium binding polymer has a MouthFeel score greater than 3.5, and wherein the crosslinked potassiumbinding polymer is characterized by a crosslinking of about 1.8%,wherein the term about means±10%.
 140. The crosslinked potassium bindingpolymer of claim 139, wherein the ratio of m to n is from about 70:1 toabout 50:1.
 141. The crosslinked potassium binding polymer of claim 139or 140, wherein the ratio of m to n is from about 70:1 to about 60:1.142. The crosslinked potassium binding polymer of any one of claims 139to 141, wherein the ratio of m to n is about 68:1.
 143. The crosslinkedpotassium binding polymer of any one of claims 139 to 142, wherein Y isphenyl.
 144. The crosslinked potassium binding polymer of any one ofclaims 139 to 143, wherein X is absent or phenyl.
 145. The crosslinkedpotassium binding polymer of any one of claims 139 to 144, wherein X isabsent and R₁ is H when XR₁ is attached to the carbon atom substitutedwith Y.
 146. The crosslinked potassium binding polymer of any one ofclaims 139 to 145, wherein R₃ is H.
 147. The crosslinked potassiumbinding polymer of any one of claims 139 to 144 and 146, wherein R₁ andR₂ are each independently H or —S(O)₂OH.
 148. The crosslinked potassiumbinding polymer of any one of claims 139 to 147, wherein the potassiumbinding polymer is characterized by a swelling ratio in water of betweenabout 3 grams of water per gram of polymer to about 8 grams of water pergram of polymer.
 149. The crosslinked potassium binding polymer of anyone of claims 139 to 148, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 4.5 grams of water per gram ofpolymer.
 150. The crosslinked potassium binding polymer of any one ofclaims 139 to 149, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of about 4.3 grams of waterper gram of polymer.
 151. The crosslinked potassium binding polymer ofany one of claims 139 to 150, wherein the particles have an averageparticle size Dv(0.9) between about 40 μm to about 70 μm.
 152. Thecrosslinked potassium binding polymer of any one of claims 139 to 151,wherein the particles have an average particle size Dv(0.9) betweenabout 50 μm to about 60 μm.
 153. The crosslinked potassium bindingpolymer of any one of claims 139 to 152, wherein the particles have anaverage particle size Dv(0.5) between about 20 μm to about 50 μm. 154.The crosslinked potassium binding polymer of any one of claims 139 to153, wherein the particles have an average particle size Dv(0.5) betweenabout 30 μm to about 40 μm.
 155. The crosslinked potassium bindingpolymer of any one of claims 139 to 154, wherein the particles have anaverage particle size Dv(0.1) between about 5 μm to about 25 μm. 156.The crosslinked potassium binding polymer of any one of claims 139 to155, wherein the particles have an average particle size Dv(0.1) betweenabout 6 μm to about 23 μm.
 157. The crosslinked potassium bindingpolymer of any one of claims 139 to 156, wherein ratio ofDv(0.9):Dv(0.5) is about two or less and the ratio of Dv(0.5):Dv(0.1) isabout five or less.
 158. The crosslinked potassium binding polymer ofany one of claims 139 to 157, wherein the ratio of Dv(0.9):Dv(0.5) andthe ratio of Dv(0.5):Dv(0.1) are each independently about two or less.159. The crosslinked potassium binding polymer of any one of claims 139to 158, wherein the potassium binding polymer has a potassium exchangecapacity from about 1 mEq to about 4 mEq per gram of potassium bindingpolymer.
 160. The crosslinked potassium binding polymer of any one ofclaims 139 to 159, wherein the potassium binding polymer has a MouthFeel score greater than 4.0.
 161. The crosslinked potassium bindingpolymer of any one of claims 139 to 160, wherein the potassium bindingpolymer has a Mouth Feel score greater than 4.5.
 162. The crosslinkedpotassium binding polymer of any one of claims 139 to 161, wherein thepotassium binding polymer has a Mouth Feel score greater than 5.0. 163.A calcium salt of a crosslinked potassium binding polymer having thestructure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each R₁ isindependently selected from the group consisting of H, —S(O)₂OH,—OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; each R₂ isindependently selected from the group consisting of H, substituted orunsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₆-C₁₈)aryl,—S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; eachR₃ is H; each X is either absent or substituted or unsubstituted(C₆-C₁₈)aryl; each Y is independently selected from the group consistingof substituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and the mole ratio of m to n is from about120:1 to about 40:1; and wherein the crosslinked potassium bindingpolymer comprises substantially spherical particles having a mediandiameter from about 20 μm to about 130 μm and wherein the crosslinkedpotassium binding polymer is characterized by a crosslinking of about1.8%, wherein the term about means±10%.
 164. The crosslinked potassiumbinding polymer of claim 163, wherein the ratio of m to n is from about70:1 to about 50:1.
 165. The crosslinked potassium binding polymer ofclaim 163 or 164, wherein the ratio of m to n is from about 70:1 toabout 60:1.
 166. The crosslinked potassium binding polymer of any one ofclaims 163 to 165, wherein the ratio of m to n is about 68:1.
 167. Thecrosslinked potassium binding polymer of any one of claims 163 to 166,wherein Y is phenyl.
 168. The crosslinked potassium binding polymer ofany one of claims 163 to 167, wherein X is absent or phenyl.
 169. Thecrosslinked potassium binding polymer of any one of claims 163 to 168,wherein X is absent and R₁ is H when XR₁ is attached to the carbon atomsubstituted with Y.
 170. The crosslinked potassium binding polymer ofany one of claims 163 to 168, wherein R₁ and R₂ are each independently Hor —S(O)₂OH.
 171. The crosslinked potassium binding polymer of any oneof claims 163 to 170, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 8 grams of water per gram of polymer.172. The crosslinked potassium binding polymer of any one of claims 163to 171, wherein the potassium binding polymer is characterized by aswelling ratio in water of between about 3 grams of water per gram ofpolymer to about 4.5 grams of water per gram of polymer.
 173. Thecrosslinked potassium binding polymer of any one of claims 163 to 172,wherein the potassium binding polymer is characterized by a swellingratio in water of about 4.3 grams of water per gram of polymer.
 174. Thecrosslinked potassium binding polymer of any one of claims 163 to 173,wherein the particles have an average particle size Dv(0.9) betweenabout 80 μm to about 130 μm.
 175. The crosslinked potassium bindingpolymer of any one of claims 163 to 174, wherein the particles have anaverage particle size Dv(0.9) between about 90 μm to about 120 μm. 176.The crosslinked potassium binding polymer of any one of claims 163 to175, wherein the particles have an average particle size Dv(0.5) betweenabout 60 μm to about 90 μm.
 177. The crosslinked potassium bindingpolymer of any one of claims 163 to 176, wherein the particles have anaverage particle size Dv(0.5) between about 70 μm to about 80 μm. 178.The crosslinked potassium binding polymer of any one of claims 163 to177, wherein the particles have an average particle size Dv(0.1) betweenabout 20 μm to about 70 μm.
 179. The crosslinked potassium bindingpolymer of any one of claims 163 to 178, wherein the particles have anaverage particle size Dv(0.1) between about 30 μm to about 60 μm. 180.The crosslinked potassium binding polymer of any one of claims 163 to179, wherein ratio of Dv(0.9):Dv(0.5) is about two or less and the ratioof Dv(0.5):Dv(0.1) is about five or less.
 181. The crosslinked potassiumbinding polymer of any one of claims 163 to 180, wherein the ratio ofDv(0.9):Dv(0.5) and the ratio of Dv(0.5):Dv(0.1) are each independentlyabout two or less.
 182. The crosslinked potassium binding polymer of anyone of claims 163 to 181, wherein the potassium binding polymer has apotassium exchange capacity from about 1 mEq to about 4 mEq per gram ofpotassium binding polymer.
 183. The crosslinked potassium bindingpolymer of any one of claims 163 to 182, wherein the potassium bindingpolymer has a Mouth Feel score greater than 3.5.
 184. The crosslinkedpotassium binding polymer of any one of claims 163 to 183, wherein thepotassium binding polymer has a Mouth Feel score greater than 4.5. 185.The crosslinked potassium binding polymer of any one of claims 163 to184, wherein the potassium binding polymer has a Mouth Feel scoregreater than 5.0.
 186. A calcium salt of a crosslinked potassium bindingpolymer having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each R₁ isindependently selected from the group consisting of H, —S(O)₂OH,—OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; each R₂ isindependently selected from the group consisting of H, substituted orunsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₆-C₁₈)aryl,—S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; eachR₃ is H; each X is either absent or substituted or unsubstituted(C₆-C₁₈)aryl; each Y is independently selected from the group consistingof substituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; and the mole ratio of m to n is from about120:1 to about 40:1; and wherein the crosslinked potassium bindingpolymer comprises substantially spherical particles having a mediandiameter from about 5 μm to about 70 μm and wherein the crosslinkedpotassium binding polymer is characterized by a crosslinking of about1.8%, wherein the term about means±10%.
 187. The crosslinked potassiumbinding polymer of claim 186, wherein the ratio of m to n is from about70:1 to about 50:1.
 188. The crosslinked potassium binding polymer ofclaim 186 or 187, wherein the ratio of m to n is from about 70:1 toabout 60:1.
 189. The crosslinked potassium binding polymer of any one ofclaims 186 to 188, wherein the ratio of m to n is about 68:1.
 190. Thecrosslinked potassium binding polymer of any one of claims 186 to 189,wherein Y is phenyl.
 191. The crosslinked potassium binding polymer ofany one of claims 186 to 190, wherein X is absent or phenyl.
 192. Thecrosslinked potassium binding polymer of any one of claims 186 to 191,wherein X is absent and R₁ is H when XR₁ is attached to the carbon atomsubstituted with Y.
 193. The crosslinked potassium binding polymer ofany one of claims 186 to 191, wherein R₁ and R₂ are each independently Hor —S(O)₂OH.
 194. The crosslinked potassium binding polymer of any oneof claims 186 to 193, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 8 grams of water per gram of polymer.195. The crosslinked potassium binding polymer of any one of claims 186to 194, wherein the potassium binding polymer is characterized by aswelling ratio in water of between about 3 grams of water per gram ofpolymer to about 4.5 grams of water per gram of polymer.
 196. Thecrosslinked potassium binding polymer of any one of claims 186 to 195,wherein the potassium binding polymer is characterized by a swellingratio in water of about 4.3 grams of water per gram of polymer.
 197. Thecrosslinked potassium binding polymer of any one of claims 186 to 196,wherein the particles have an average particle size Dv(0.9) betweenabout 40 μm to about 70 μm.
 198. The crosslinked potassium bindingpolymer of any one of claims 186 to 197, wherein the particles have anaverage particle size Dv(0.9) between about 50 μm to about 60 μm. 199.The crosslinked potassium binding polymer of any one of claims 186 to198, wherein the particles have an average particle size Dv(0.5) betweenabout 20 μm to about 50 μm.
 200. The crosslinked potassium bindingpolymer of any one of claims 186 to 199, wherein the particles have anaverage particle size Dv(0.5) between about 30 μm to about 40 μm. 201.The crosslinked potassium binding polymer of any one of claims 186 to200, wherein the particles have an average particle size Dv(0.1) betweenabout 5 μm to about 25 μm.
 202. The crosslinked potassium bindingpolymer of any one of claims 186 to 201, wherein the particles have anaverage particle size Dv(0.1) between about 6 μm to about 23 μm. 203.The crosslinked potassium binding polymer of any one of claims 186 to202, wherein ratio of Dv(0.9):Dv(0.5) is about two or less and the ratioof Dv(0.5):Dv(0.1) is about five or less.
 204. The crosslinked potassiumbinding polymer of any one of claims 186 to 203, wherein the ratio ofDv(0.9):Dv(0.5) and the ratio of Dv(0.5):Dv(0.1) are each independentlyabout two or less.
 205. The crosslinked potassium binding polymer of anyone of claims 186 to 204, wherein the potassium binding polymer has apotassium exchange capacity from about 1 mEq to about 4 mEq per gram ofpotassium binding polymer.
 206. The crosslinked potassium bindingpolymer of any one of claims 186 to 205, wherein the potassium bindingpolymer has a Mouth Feel score greater than 3.5.
 207. The crosslinkedpotassium binding polymer of any one of claims 186 to 206, wherein thepotassium binding polymer has a Mouth Feel score greater than 4.5. 208.The crosslinked potassium binding polymer of any one of claims 186 to207, wherein the potassium binding polymer has a Mouth Feel scoregreater than 5.0.
 209. A pharmaceutical composition comprising acrosslinked potassium binding polymer of any one of claims 1 to 208 anda pharmaceutically acceptable carrier, diluent, or excipient.
 210. Apharmaceutical composition comprising a calcium salt of a crosslinkedpotassium binding polymer that has a potassium exchange capacity fromabout 1 mEq to about 4 mEq per gram of potassium binding polymer and apharmaceutically acceptable carrier, diluent, or excipient, wherein thepotassium binding polymer is characterized by a swelling ratio in waterof between about 3 grams of water per gram of polymer to about 8 gramsof water per gram of polymer and a crosslinking of less than 5% andwherein the polymer comprises substantially spherical particles and issubstantially endotoxin free.
 211. The composition of claim 210, whereinthe substantially spherical particles have a median diameter from about1 μm to about 130 μm when said particles are in their calcium salt formand swollen in water.
 212. The composition of claim 211, wherein themedian diameter is from about 60 μm to about 90 μm.
 213. The compositionof claim 211 or 212, wherein the particles have a median diameter fromabout 70 μm to about 80 μm.
 214. The composition of any one of claims211 to 213, wherein the median diameter is about 75 μm.
 215. Thecomposition of claim 211 or 212, wherein the median diameter is fromabout 20 μm to about 50 μm.
 216. The composition of claim 215, whereinthe median diameter is from about 30 μm to about 40 μm.
 217. Thecomposition of claim 215 or 216, wherein the median diameter is about 35μm.
 218. The composition of any one of claims 210 to 217, wherein thepotassium binding polymer is characterized by a crosslinking of lessthan 3%.
 219. The composition of any one of claims 210 to 218, whereinthe potassium binding polymer is characterized by a crosslinking ofabout 1.8%, wherein the term about means±20%.
 220. The composition ofany one of claims 210 to 218, wherein the potassium binding polymer ischaracterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.
 221. The composition of any one of claims 210 to 218, whereinthe potassium binding polymer is characterized by a crosslinking ofabout 1.8%, wherein the term about means±5%.
 222. The composition of anyone of claims 210 to 218, wherein the potassium binding polymer ischaracterized by a crosslinking of 1.8%.
 223. The composition of claimof any one of claims 210 to 222, wherein the potassium binding polymerhas a Mouth Feel score greater than 4.5.
 224. The composition of claimof any one of claims 210 to 223, wherein the potassium binding polymerhas a Mouth Feel score greater than 5.0.
 225. A pharmaceuticalcomposition comprising a calcium salt of a crosslinked potassium bindingpolymer that has a potassium exchange capacity from about 1 mEq to about4 mEq per gram of potassium binding polymer and a pharmaceuticallyacceptable carrier, diluent, or excipient, wherein the potassium bindingpolymer is characterized by a swelling ratio in water of between about 3grams of water per gram of polymer to about 8 grams of water per gram ofpolymer and a crosslinking of less than 5%.
 226. The composition ofclaim 225, wherein the polymer comprises substantially sphericalparticles.
 227. The composition of claim 226, wherein the substantiallyspherical particles have a median diameter from about 1 μm to about 130μm when said particles are in their calcium salt form and swollen inwater.
 228. The composition of claim 227, wherein the median diameter isfrom about 60 μm to about 90 μm.
 229. The composition of claim 227 or228, wherein the particles have a median diameter from about 70 μm toabout 80 μm.
 230. The composition of any one of claims 227 to 229,wherein the median diameter is about 75 μm.
 231. The composition ofclaim 227 or 228, wherein the median diameter is from about 20 μm toabout 50 μm.
 232. The composition of claim 231, wherein the mediandiameter is from about 30 μm to about 40 μm.
 233. The composition ofclaim 231 or 232, wherein the median diameter is about 35 μm.
 234. Thecomposition of any one of claims 225 to 233, wherein the potassiumbinding polymer is characterized by a crosslinking of less than 3%. 235.The composition of any one of claims 225 to 234, wherein the potassiumbinding polymer is characterized by a crosslinking of about 1.8%,wherein the term about means±20%.
 236. The composition of any one ofclaims 225 to 234, wherein the potassium binding polymer ischaracterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.
 237. The composition of any one of claims 225 to 234, whereinthe potassium binding polymer is characterized by a crosslinking ofabout 1.8%, wherein the term about means±5%.
 238. The composition of anyone of claims 225 to 234, wherein the potassium binding polymer ischaracterized by a crosslinking of 1.8%.
 239. The composition of claimof any one of claims 225 to 238, wherein the potassium binding polymerhas a Mouth Feel score greater than 4.5.
 240. The composition of claimof any one of claims 225 to 239, wherein the potassium binding polymerhas a Mouth Feel score greater than 5.0.
 241. A pharmaceuticalcomposition comprising a calcium salt of a crosslinked potassium bindingpolymer that has a potassium exchange capacity from about 1 mEq to about4 mEq per gram of potassium binding polymer and a pharmaceuticallyacceptable carrier, diluent, or excipient, wherein the potassium bindingpolymer is characterized by a crosslinking of less than 5% and aswelling ratio in water of between about 3 grams of water per gram ofpolymer to about 8 grams of water per gram of polymer.
 242. Thecomposition of claim 241, wherein the polymer comprises substantiallyspherical particles.
 243. The composition of claim 242, wherein thesubstantially spherical particles have a median diameter from about 1 μmto about 130 μm when said particles are in their calcium salt form andswollen in water.
 244. The composition of claim 243, wherein the mediandiameter is from about 60 μm to about 90 μm.
 245. The composition ofclaim 243 or 244, wherein the particles have a median diameter fromabout 70 μm to about 80 μm.
 246. The composition of any one of claims243 to 245, wherein the median diameter is about 75 μm.
 247. Thecomposition of claim 243 or 244, wherein the median diameter is fromabout 20 μm to about 50 μm.
 248. The composition of claim 247, whereinthe median diameter is from about 30 μm to about 40 μm.
 249. Thecomposition of claim 247 or 248, wherein the median diameter is about 35μm.
 250. The composition of claim of any one of claims 241 to 249,wherein the potassium binding polymer is characterized by a crosslinkingof about 1.8%, wherein the term about means±10%.
 251. The composition ofclaim of any one of claims 241 to 250, wherein the potassium bindingpolymer has a Mouth Feel score greater than 4.5.
 252. The composition ofclaim of any one of claims 231 to 251, wherein the potassium bindingpolymer has a Mouth Feel score greater than 5.0.
 253. A pharmaceuticalcomposition comprising a calcium salt of a crosslinked potassium bindingpolymer that has a potassium exchange capacity from about 1 mEq to about4 mEq per gram of potassium binding polymer and a pharmaceuticallyacceptable carrier, diluent, or excipient, wherein the potassium bindingpolymer is characterized by a crosslinking of less than 5% and whereinmedian diameter is from about 1 μm to about 130 μm when said particlesare in their calcium salt form and swollen in water.
 254. Thecomposition of claim 253, wherein the polymer comprises substantiallyspherical particles.
 255. The composition of claim 254, wherein thesubstantially spherical particles have a median diameter from about 1 μmto about 120 μm when said particles are in their calcium salt form andswollen in water.
 256. The composition of claim 255, wherein the mediandiameter is from about 60 μm to about 90 μm.
 257. The composition ofclaim 255 or 256, wherein the median diameter from about 70 μm to about80 μm.
 258. The composition of any one of claims 255 to 257, wherein themedian diameter is about 75 μm.
 259. The composition of claim 255 or256, wherein the median diameter is from about 20 μm to about 50 μm.260. The composition of claim 259, wherein the median diameter is fromabout 30 μm to about 40 μm.
 261. The composition of claim 259 or 260,wherein the median diameter is about 35 μm.
 262. The composition of anyone of claims 253 to 261, wherein the potassium binding polymer ischaracterized by a crosslinking of less than 2%.
 263. The composition ofany one of claims 253 to 262, wherein the potassium binding polymer ischaracterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%.
 264. The composition of claim of any one of claims 253 to263, wherein the potassium binding polymer has a Mouth Feel scoregreater than 4.5.
 265. The composition of claim of any one of claims 253to 264, wherein the potassium binding polymer has a Mouth Feel scoregreater than 5.0.
 266. A pharmaceutical composition comprising a calciumsalt of a crosslinked potassium binding polymer and a pharmaceuticallyacceptable carrier, diluent, or excipient, wherein the crosslinkedpotassium binding polymer is characterized by a crosslinking of lessthan 5% and wherein median diameter is from about 1 μm to about 130 μmwhen said particles are in their calcium salt form and swollen in water.267. The composition of claim 266 wherein the composition once swollencomprises between 3 and 5 grams of water per gram of polymer.
 268. Thecomposition of any one of claims 210 to 267, wherein said polymer is astyrene polymer.
 269. The composition of any one of claims 210 to 268,wherein said polymer is crosslinked with divinyl benzene.
 270. Thecomposition of claim 269, wherein the divinyl benzene is divinyl benzenesulfonate.
 271. The composition of any one of claims 210 to 270, whereinsaid polymer is a salt of crosslinked polystyrene sulfonate.
 272. Thecomposition of any one of claims 210 to 271, wherein said composition isfurther substantially active as a phosphate binder.
 273. The compositionof claim 272, wherein said polymer has a capacity to increase fecalphosphorous output in a subject.
 274. The composition of claim 272,wherein said polymer has a capacity to decrease urinary phosphorousoutput in a subject.
 275. A method for removing potassium from thegastrointestinal tract of a patient showing clinical signs ofhyperkalemia or suspected of having hyperkalemia, comprisingadministering a calcium salt of a crosslinked potassium binding polymer,or salt thereof, to the patient, wherein the potassium binding polymercomprises at least one monomer and one crosslinker, the crosslinkercomprising from about 1 mole % to about 3 mole % of the potassiumbinding polymer and wherein the potassium binding polymer ischaracterized by a crosslinking of less than 5%.
 276. The method ofclaim 275, wherein the at least one crosslinker comprises from about 1.5mole % to about 2.0 mole % of the potassium binding polymer.
 277. Themethod of claim 276, wherein the at least one crosslinker comprises fromabout 1.5 mole % to about 1.6 mole % of the potassium binding polymer.278. The method of claim 275, wherein the at least one crosslinkercomprises about 1.5 mole % of the potassium binding polymer.
 279. Themethod of any one of claims 275 to 278, wherein the at least onecrosslinker is divinyl benzene sulfonate.
 280. The method of any one ofclaims 275 to 279, wherein the at least one monomer is styrenesulfonate.
 281. The method of any one of claims 275 to 280, wherein thepotassium binding polymer is a salt of crosslinked polystyrenesulfonate.
 282. The method of any one of claims 275 to 281, wherein thepotassium binding polymer is characterized by a swelling ratio in waterof between about 3 grams of water per gram of polymer to 4.5 grams ofwater per gram of polymer.
 283. The method of any one of claims 275 to282, wherein the potassium binding polymer further comprisessubstantially spherical particles having a median diameter from about 1μm to about 120 μm when said particles are in their calcium salt formand swollen in water.
 284. The method of claim 283, wherein the mediandiameter is from about 60 μm to about 90 μm.
 285. The method of claim283 or 284, wherein the median diameter from about 70 μm to about 80 μm.286. The method of any one of claims 283 to 285, wherein the mediandiameter is about 75 μm.
 287. The method of claim 283 or 284, whereinthe median diameter is from about 20 μm to about 50 μm.
 288. The methodof claim 287, wherein the median diameter is from about 30 μm to about40 μm.
 289. The method of claim 287 or 288, wherein the median diameteris about 35 μm.
 290. The method of any one of claims 275 to 289, whereinratio of Dv(0.9):Dv(0.5) is about two or less and the ratio ofDv(0.5):Dv(0.1) is about five or less.
 291. The method of any one ofclaims 275 to 290, wherein the ratio of Dv(0.9):Dv(0.5) and the ratio ofDv(0.5):Dv(0.1) are each independently about two or less.
 292. Themethod of any one of claims 275 to 291, wherein the potassium bindingpolymer has a potassium exchange capacity from about 1 mEq to about 4mEq per gram of potassium binding polymer.
 293. The method of any one ofclaims 275 to 292, wherein the potassium binding polymer ischaracterized by a crosslinking of less than 2%.
 294. The method of anyone of claims 275 to 292, wherein the potassium binding polymer ischaracterized by a crosslinking of about 1.8%, wherein the term aboutmeans±10%
 295. The method of any one of claims 275 to 294, wherein thepatient is experiencing hyperkalemia.
 296. The method of any one ofclaims 275 to 295, wherein the patient is a human.
 297. A method forremoving potassium from the gastrointestinal tract of a patient showingclinical signs of hyperkalemia or suspected of having hyperkalemia,comprising administering a calcium salt of a crosslinked potassiumbinding polymer, or salt thereof, to the patient, wherein the potassiumbinding polymer comprises at least one monomer and one crosslinker,wherein the potassium binding polymer comprises substantially sphericalparticles having a median diameter from about 1 μm to about 25 μm, andwherein the crosslinked potassium binding polymer is characterized by acrosslinking of less than 5%.
 298. The method of claim 297, wherein themedian diameter is from about 10 μm to about 20 μm.
 299. The method ofclaim 297 or 298, wherein the median diameter is about 15 μm.
 300. Themethod of any one of claims 297 to 299, wherein ratio of Dv(0.9):Dv(0.5)is about two or less and the ratio of Dv(0.5):Dv(0.1) is about five orless.
 301. The method of any one of claims 297 to 300, wherein the ratioof Dv(0.9):Dv(0.5) and the ratio of Dv(0.5):Dv(0.1) are eachindependently about two or less.
 302. The method of any one of claims297 to 301, wherein the at least one crosslinker comprises from about 1mole % to about 11 mole % of the potassium binding polymer.
 303. Themethod of any one of claims 297 to 301, wherein the at least onecrosslinker comprises from about 1 mole % to about 7 mole % of thepotassium binding polymer.
 304. The method of any one of claims 297 to301, wherein the at least one crosslinker comprises from about 1 mole %to about 3 mole % of the potassium binding polymer.
 305. The method ofany one of claims 297 to 301, wherein the at least one crosslinkercomprises from about 1.5 mole % to about 2.0 mole % of the potassiumbinding polymer.
 306. The method of any one of claims 297 to 301,wherein the at least one crosslinker comprises from about 1.5 mole % toabout 1.6 mole % of the potassium binding polymer.
 307. The method ofclaim any one of claims 297 to 301, wherein the at least one crosslinkercomprises about 1.5 mole % of the potassium binding polymer.
 308. Themethod of any one of claims 297 to 307, wherein the at least onecrosslinker is divinyl benzene sulfonate.
 309. The method of any one ofclaims 297 to 308, wherein the at least one monomer is styrenesulfonate.
 310. The method of any one of claims 297 to 309, wherein thepotassium binding polymer is a salt of crosslinked polystyrenesulfonate.
 311. The method of any one of claims 297 to 310, wherein thepotassium binding polymer is characterized by a swelling ratio in waterof between about 3 grams of water per gram of polymer to 4.5 grams ofwater per gram of polymer.
 312. The method of any one of claims 297 to311, wherein the potassium binding polymer has a potassium exchangecapacity from about 1 mEq to about 4 mEq per gram of potassium bindingpolymer.
 313. The method of any one of claims 297 to 312, wherein thepotassium binding polymer is characterized by a crosslinking of lessthan 2%.
 314. The method of any one of claims 297 to 312, wherein thepotassium binding polymer is characterized by a crosslinking of about1.8%, wherein the term about means±10%
 315. The method of any one ofclaims 297 to 314, wherein the patient is experiencing hyperkalemia.316. The method of any one of claims 297 to 315, wherein the patient isa human.
 317. A method for removing potassium from the gastrointestinaltract of a patient showing clinical signs of hyperkalemia or suspectedof having hyperkalemia, comprising administering of a calcium salt of apotassium binding polymer, or salt thereof, to the patient, wherein thecrosslinked potassium binding polymer has a structure of Formula (I):

wherein: each R₁ is independently selected from the group consisting ofH, substituted or unsubstituted (C₁-C₆) alkyl, substituted orunsubstituted (C₆-C₁₈) aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH, —PO(OH)₂,—OP(OH)₃, and —NHS(O)₂OH; each R₂ is independently selected from thegroup consisting of H, substituted or unsubstituted (C₁-C₆)alkyl,substituted or unsubstituted (C₆-C₁₈)aryl, —S(O)₂OH, —OS(O)₂OH, —C(O)OH,—PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; each R₃ is independently selectedfrom the group consisting of H, halogen, substituted or unsubstituted(C₁-C₆)alkyl, substituted or unsubstituted (C₆-C₁₈)aryl, —S(O)₂OH,—OS(O)₂OH, —C(O)OH, —PO(OH)₂, —OP(OH)₃, and —NHS(O)₂OH; each X is eitherabsent or independently selected from the group consisting ofsubstituted or unsubstituted (C₁-C₆)alkyl and substituted orunsubstituted (C₆-C₁₈)aryl; each Y is independently selected from thegroup consisting of substituted or unsubstituted (C₁-C₆)alkyl andsubstituted or unsubstituted (C₆-C₁₈)aryl; and the mole ratio of m to nis from about 120:1 to about 40:1 wherein the crosslinked potassiumbinding polymer is characterized by a crosslinking of less than 5%. 318.The method of claim 317, wherein the ratio of m to n is from about 70.1to about 50:1.
 319. The method of claim 317 or 31/, wherein the ratio ofm to n is from about 70:1 to about 60:1.
 320. The method of any one ofclaims 317 to 319, wherein the ratio of m to n is about 68:1.
 321. Themethod of any one of claims 317 to 320, wherein Y is phenyl.
 322. Themethod of any one of claims 317 to 321, wherein X is absent or phenyl.323. The method of any one of claims 317 to 322, wherein X is absent andR₁ is H when XR₁ is attached to the carbon atom substituted with Y. 324.The method of any one of claims 317 to 323, wherein R₁ and R₂ are—S(O)₂OH.
 325. The method of any one of claims 317 to 324, wherein thepotassium binding polymer is characterized by a swelling ratio in waterof between about 3 grams of water per gram of polymer to about 8 gramsof water per gram of polymer.
 326. The method of any one of claims 317to 325, wherein the potassium binding polymer is characterized by aswelling ratio in water of between about 3 grams of water per gram ofpolymer to about 4.5 grams of water per gram of polymer.
 327. The methodof any one of claims 317 to 326, wherein the potassium binding polymerfurther comprises substantially spherical particles having a mediandiameter from about 1 μm to about 130 μm.
 328. The method of claim 327,wherein the median diameter is from about 60 μm to about 90 μm.
 329. Themethod of claim 327 or 328, wherein the median diameter from about 70 μmto about 80 μm.
 330. The method of any one of claims 327 to 329, whereinthe median diameter is about 75 μm.
 331. The method of claim 327,wherein the median diameter is from about 20 μm to about 50 μm.
 332. Themethod of 327 or 331, wherein the median diameter is from about 30 μm toabout 40 μm.
 333. The method of any one of claims 327, 331, and 332,wherein the median diameter is about 35 μm.
 334. The method of any oneof claims 317 to 333, wherein ratio of Dv(0.9):Dv(0.5) is about two orless and the ratio of Dv(0.5):Dv(0.1) is about five or less.
 335. Themethod of any one of claims 317 to 334, wherein the ratio ofDv(0.9):Dv(0.5) and the ratio of Dv(0.5):Dv(0.1) are each independentlyabout two or less.
 336. The method of any one of claims 317 to 335,wherein the potassium binding polymer has a potassium exchange capacityfrom about 1 mEq to about 4 mEq per gram of potassium binding polymer.337. The method of any one of claims 317 to 336, wherein the potassiumbinding polymer is characterized by a crosslinking of less than 2%. 338.The method of any one of claims 317 to 337, wherein the potassiumbinding polymer is characterized by a crosslinking of about 1.8%,wherein the term about means±10%
 339. The method of any one of claims317 to 338, wherein the patient is experiencing hyperkalemia.
 340. Themethod of any one of claims 317 to 339, wherein the patient is a human.341. A method for removing potassium from the gastrointestinal tract ofa patient showing clinical signs of hyperkalemia or suspected of havinghyperkalemia, comprising administering to the patient a crosslinkedpotassium binding polymer, or salt thereof, of any one of claims 1, 38,68, 92, 116, 139, 163, and
 186. 342. A calcium salt of a crosslinkedpotassium binding polymer having the following structure:

or a pharmaceutically acceptable salt thereof, wherein the mole ratio ofm to n is from about 120:1 to about 40:1; and wherein the crosslinkedpotassium binding polymer is characterized by a crosslinking of lessthan 5%.
 343. The crosslinked potassium binding polymer of claim 342,wherein the ratio of m to n is from about 70:1 to about 50:1.
 344. Thecrosslinked potassium binding polymer of claim 342 or 343, wherein theratio of m to n is from about 70:1 to about 60:1.
 345. The crosslinkedpotassium binding polymer of any one of claims 342 to 344, wherein theratio of m to n is about 68:1.
 346. The crosslinked potassium bindingpolymer of any one of claims 342 to 345, wherein the potassium bindingpolymer is characterized by a swelling ratio in water of between about 3grams of water per gram of polymer to about 8 grams of water per gram ofpolymer.
 347. The crosslinked potassium binding polymer of any one ofclaims 342 to 346, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 4.5 grams of water per gram ofpolymer.
 348. The crosslinked potassium binding polymer of any one ofclaims 342 to 347, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of about 3.3 grams of waterper gram of polymer.
 349. The crosslinked potassium binding polymer ofany one of claims 342 to 347, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of about 4.3 grams of waterper gram of polymer.
 350. The crosslinked potassium binding polymer ofany one of claims 342 to 349, wherein the potassium binding polymerfurther comprises substantially spherical particles having a mediandiameter from about 5 μm to about 130 μm.
 351. The crosslinked potassiumbinding polymer of claim 350, wherein the particles have an averageparticle size Dv(0.9) between about 80 μm to about 130 μm.
 352. Thecrosslinked potassium binding polymer of claim 350 or 351, wherein theparticles have an average particle size Dv(0.9) between about 90 μm toabout 120 μm.
 353. The crosslinked potassium binding polymer of claim350, wherein the particles have an average particle size Dv(0.9) betweenabout 40 μm to about 70 μm.
 354. The crosslinked potassium bindingpolymer of claim 350 or 353, wherein the particles have an averageparticle size Dv(0.9) between about 50 μm to about 60 μm.
 355. Thecrosslinked potassium binding polymer of any one of claims 350 to 354,wherein the particles have an average particle size Dv(0.5) betweenabout 60 μm to about 90 μm.
 356. The crosslinked potassium bindingpolymer of any one of claims 350 to 355, wherein the particles have anaverage particle size Dv(0.5) between about 70 μm to about 80 μm. 357.The crosslinked potassium binding polymer of any one of claims 350 to354, wherein the particles have an average particle size Dv(0.5) betweenabout 20 μm to about 50 μm.
 358. The crosslinked potassium bindingpolymer of any one of claims 350 to 354 and 357, wherein the particleshave an average particle size Dv(0.5) between about 30 μm to about 40μm.
 359. The crosslinked potassium binding polymer of any one of claims350 to 358, wherein the particles have an average particle size Dv(0.1)between about 20 μm to about 70 μm.
 360. The crosslinked potassiumbinding polymer of any one of claims 350 to 359, wherein the particleshave an average particle size Dv(0.1) between about 30 μm to about 60μm.
 361. The crosslinked potassium binding polymer of any one of claims350 to 358, wherein the particles have an average particle size Dv(0.1)between about 5 μm to about 30 μm.
 362. The crosslinked potassiumbinding polymer of any one of claims 350 to 358 and 361, wherein theparticles have an average particle size Dv(0.1) between about 6 μm toabout 23 μm.
 363. The crosslinked potassium binding polymer of any oneof claims 342 to 362, wherein ratio of Dv(0.9):Dv(0.5) is about two orless and the ratio of Dv(0.5):Dv(0.1) is about five or less.
 364. Thecrosslinked potassium binding polymer of any one of claims 342 to 363,wherein the ratio of Dv(0.9):Dv(0.5) and the ratio of Dv(0.5):Dv(0.1)are each independently about two or less.
 365. The crosslinked potassiumbinding polymer of any one of claims 342 to 364, wherein the potassiumbinding polymer has a potassium exchange capacity from about 1 mEq toabout 4 mEq per gram of potassium binding polymer.
 366. The crosslinkedpotassium binding polymer of any one of claims 342 to 365, wherein thepotassium binding polymer has a Mouth Feel score greater than 3.5. 367.The crosslinked potassium binding polymer of any one of claims 342 to366, wherein the potassium binding polymer has a Mouth Feel scoregreater than 4.5.
 368. The crosslinked potassium binding polymer of anyone of claims 342 to 367, wherein the potassium binding polymer has aMouth Feel score greater than 5.0.
 369. The crosslinked potassiumbinding polymer of any one of claims 342 to 368, wherein the potassiumbinding polymer is characterized by a crosslinking of less than 3%. 370.The crosslinked potassium binding polymer of any one of claims 342 to368, wherein the potassium binding polymer is characterized by acrosslinking of about 1.8%, wherein the term about means±20%.
 371. Thecrosslinked potassium binding polymer of any one of claims 342 to 368,wherein the potassium binding polymer is characterized by a crosslinkingof about 1.8%, wherein the term about means±10%.
 372. The crosslinkedpotassium binding polymer of any one of claims 342 to 368, wherein thepotassium binding polymer is characterized by a crosslinking of about1.8%, wherein the term about means±5%.
 373. The crosslinked potassiumbinding polymer of any one of claims 342 to 368, wherein the potassiumbinding polymer is characterized by a crosslinking of 1.8%.
 374. Apharmaceutical composition comprising: i) about 86.5% to about 91% of acalcium salt of a crosslinked potassium binding polymer having thefollowing structure:

or a pharmaceutically acceptable salt thereof, wherein the mole ratio ofm to n is from about 120:1 to about 40:1; and wherein the crosslinkedpotassium binding polymer is characterized by a crosslinking of lessthan 5%; ii) about 2.0% to about 3.0% of calcium citrate tetrahydrate;iii) about 2.0% to about 3.0% of anhydrous citric acid; iv) about 0.1%to about 1.0% of sucralose; v) about 2.0% to about 3.0% of artificialorange flavored powder; and vi) about 2.5% to about 3.5% of methylcellulose A4C.
 375. A pharmaceutical composition comprising: i) about86.5% to about 91% of a calcium salt of a crosslinked potassium bindingpolymer of Formula (I) or a pharmaceutically acceptable salt thereof;ii) about 2.0% to about 3.0% of calcium citrate tetrahydrate; iii) about2.0% to about 3.0% of anhydrous citric acid; iv) about 0.1% to about 1%of sucralose; v) about 2.0% to about 3.0% of artificial orange flavoredpowder; and vi) about 2.5% to about 3.5% of methyl cellulose A4C.
 376. Apharmaceutical composition comprising: i) about 89% to about 94.5% of acalcium salt of a crosslinked potassium binding polymer having thefollowing structure:

or a pharmaceutically acceptable salt thereof, wherein the mole ratio ofm to n is from about 120:1 to about 40:1; and wherein the crosslinkedpotassium binding polymer is characterized by a crosslinking of lessthan 5%; ii) about 0.6% to about 1.6% of calcium citrate tetrahydrate;iii) about 0.02% to about 0.5% of anhydrous citric acid; iv) about 0.1%to about 1% of sucralose; v) about 0.6% to about 1.6% of vanillinpowder; vi) about 2.5% to about 3.5% of methyl cellulose A4C; and vii)about 1.6% to about 2.6% of titanium dioxide.
 377. A pharmaceuticalcomposition comprising: i) about 89% to about 94.5% of a calcium salt ofa crosslinked potassium binding polymer of Formula (I) or apharmaceutically acceptable salt thereof; ii) about 0.6% to about 1.6%of calcium citrate tetrahydrate; iii) about 0.02% to about 0.5% ofanhydrous citric acid; iv) about 0.1% to about 1% of sucralose; v) about0.6% to about 1.6% of vanillin powder; vi) about 2.5% to about 3.5% ofmethyl cellulose A4C; and vii) about 1.6% to about 2.6% of titaniumdioxide.
 378. A pharmaceutical composition comprising: i) about 10% toabout 26% of a calcium salt of a crosslinked potassium binding polymerhaving the following structure:

or a pharmaceutically acceptable salt thereof, wherein the mole ratio ofm to n is from about 120:1 to about 40:1; and wherein the crosslinkedpotassium binding polymer is characterized by a crosslinking of lessthan 5%; ii) about 0.1% to about 1.0% of calcium citrate tetrahydrate;iii) about 0.015% to about 0.15% of benzoic acid; iv) about 0.1% toabout 1% of anhydrous citric acid; v) about 0.015% to about 0.15% ofsucralose; vi) about 0.1% to about 1.0% of natural orange WONF FV7466;vii) about 0.1% to about 1.0% of xanthan gum cp; and viii) about 73.7%to about 85.57% of water.
 379. A pharmaceutical composition comprising:i) about 10% to about 26% of a calcium salt of a crosslinked potassiumbinding polymer of Formula (I) or a pharmaceutically acceptable saltthereof; ii) about 0.1% to about 1.0% of calcium citrate tetrahydrate;iii) about 0.015% to about 0.15% of benzoic acid; iv) about 0.1% toabout 1% of anhydrous citric acid; v) about 0.015% to about 0.15% ofsucralose, vi) about 0.1% to about 1.0% of natural orange WONF FV7466;vii) about 0.1% to about 1.0% of xanthan gum cp; and viii) about 73.7%to about 85.57% of water.
 380. A pharmaceutical composition comprising:i) about 10% to about 26% of a calcium salt of a crosslinked potassiumbinding polymer having the following structure:

or a pharmaceutically acceptable salt thereof, wherein the mole ratio ofm to n is from about 120:1 to about 40:1; and wherein the crosslinkedpotassium binding polymer is characterized by a crosslinking of lessthan 5%; ii) about 0.01% to about 0.5% of calcium citrate tetrahydrate;iii) about 0.01% to about 0.1% of sorbic acid; iv) about 0.001% to about0.1% of anhydrous citric acid; v) about 0.05% to about 0.15% ofsucralose; vi) about 0.1% to about 1.0% of SuperVan art vanilla VM36;vii) about 0.1% to about 1.0% of xanthan gum cp; viii) about 0.1% toabout 1.0% of titanium dioxide; and ix) about 73.2% to about 86.65% ofwater.
 381. A pharmaceutical composition comprising: i) about 10% toabout 26% of a calcium salt of a crosslinked potassium binding polymerof Formula (I) or a pharmaceutically acceptable salt thereof; ii) about0.01% to about 0.5% of calcium citrate tetrahydrate; iii) about 0.01% toabout 0.1% of sorbic acid; iv) about 0.001% to about 0.1% of anhydrouscitric acid; v) about 0.05% to about 0.15% of sucralose; vi) about 0.1%to about 1.0% of SuperVan art vanilla VM36; vii) about 0.1% to about1.0% of xanthan gum cp; viii) about 0.1% to about 1.0% of titaniumdioxide, and ix) about 73.2% to about 86.65% of water.
 382. Thepharmaceutical composition of any one of claims 374 to 381, wherein theratio of m to n is from about 70:1 to about 50:1.
 383. Thepharmaceutical composition of any one of claims 374 to 382, wherein theratio of m to n is from about 70:1 to about 60:1.
 384. Thepharmaceutical composition of any one of claims 374 to 383, wherein theratio of m to n is about 68:1.
 385. The pharmaceutical composition ofany one of claims 374 to 384, wherein the potassium binding polymer ischaracterized by a swelling ratio in water of between about 3 grams ofwater per gram of polymer to about 8 grams of water per gram of polymer.386. The pharmaceutical composition of any one of claims 374 to 385,wherein the potassium binding polymer is characterized by a swellingratio in water of between about 3 grams of water per gram of polymer toabout 4.5 grams of water per gram of polymer.
 387. The pharmaceuticalcomposition of any one of claims 374 to 386, wherein the potassiumbinding polymer is characterized by a swelling ratio in water of about3.3 grams of water per gram of polymer.
 388. The pharmaceuticalcomposition of any one of claims 374 to 386, wherein the potassiumbinding polymer is characterized by a swelling ratio in water of about4.3 grams of water per gram of polymer.
 389. The pharmaceuticalcomposition of any one of claims 374 to 388, wherein the potassiumbinding polymer further comprises substantially spherical particleshaving a median diameter from about 5 μm to about 130 μm.
 390. Thepharmaceutical composition of any one of claims 374 to 389, wherein theparticles have an average particle size Dv(0.9) between about 80 μm toabout 130 μm.
 391. The pharmaceutical composition of any one of claims374 to 390, wherein the particles have an average particle size Dv(0.9)between about 90 μm to about 120 μm.
 392. The pharmaceutical compositionof any one of claims 374 to 388, wherein the particles have an averageparticle size Dv(0.9) between about 40 μm to about 70 μm.
 393. Thepharmaceutical composition of any one of claims 374 to 388 and 392,wherein the particles have an average particle size Dv(0.9) betweenabout 50 μm to about 60 μm.
 394. The pharmaceutical composition of anyone of claims 374 to 393, wherein the particles have an average particlesize Dv(0.5) between about 60 μm to about 90 μm.
 395. The pharmaceuticalcomposition of any one of claims 374 to 394, wherein the particles havean average particle size Dv(0.5) between about 70 μm to about 80 μm.396. The pharmaceutical composition of any one of claims 374 to 393,wherein the particles have an average particle size Dv(0.5) betweenabout 20 μm to about 50 μm.
 397. The pharmaceutical composition of anyone of claims 374 to 393 and 396, wherein the particles have an averageparticle size Dv(0.5) between about 30 μm to about 40 μm.
 398. Thepharmaceutical composition of any one of claims 374 to 397, wherein theparticles have an average particle size Dv(0.1) between about 20 μm toabout 70 μm.
 399. The pharmaceutical composition of any one of claims374 to 398, wherein the particles have an average particle size Dv(0.1)between about 30 μm to about 60 μm.
 400. The pharmaceutical compositionof any one of claims 374 to 397, wherein the particles have an averageparticle size Dv(0.1) between about 5 μm to about 30 μm.
 401. Thepharmaceutical composition of any one of claims 374 to 397 and 400,wherein the particles have an average particle size Dv(0.1) betweenabout 6 μm to about 23 μm.
 402. The pharmaceutical composition of anyone of claims 374 to 401, wherein ratio of Dv(0.9):Dv(0.5) is about twoor less and the ratio of Dv(0.5):Dv(0.1) is about five or less.
 403. Thepharmaceutical composition of any one of claims 374 to 402, wherein theratio of Dv(0.9):Dv(0.5) and the ratio of Dv(0.5):Dv(0.1) are eachindependently about two or less.
 404. The pharmaceutical composition ofany one of claims 374 to 403, wherein the potassium binding polymer hasa potassium exchange capacity from about 1 mEq to about 4 mEq per gramof potassium binding polymer.
 405. The pharmaceutical composition of anyone of claims 374 to 404, wherein the potassium binding polymer has aMouth Feel score greater than 3.5.
 406. The pharmaceutical compositionof any one of claims 374 to 405, wherein the potassium binding polymerhas a Mouth Feel score greater than 4.5.
 407. The pharmaceuticalcomposition of any one of claims 374 to 406, wherein the potassiumbinding polymer has a Mouth Feel score greater than 5.0.
 408. Thepharmaceutical composition of any one of claims 374 to 407, wherein thepotassium binding polymer is characterized by a crosslinking of lessthan 3%.
 409. The pharmaceutical composition of any one of claims 374 to408, wherein the potassium binding polymer is characterized by acrosslinking of about 1.8%, wherein the term about means±20%.
 410. Thepharmaceutical composition of any one of claims 374 to 408, wherein thepotassium binding polymer is characterized by a crosslinking of about1.8%, wherein the term about means±10%.
 411. The pharmaceuticalcomposition of any one of claims 374 to 408, wherein the potassiumbinding polymer is characterized by a crosslinking of about 1.8%,wherein the term about means±5%.
 412. The pharmaceutical composition ofany one of claims 374 to 408, wherein the potassium binding polymer ischaracterized by a crosslinking of 1.8%.